2-pyridyloxy-4-ether orexin receptor antagonists

ABSTRACT

The present invention is directed to 2-pyridyloxy-4-ether compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the 2-pyridyloxy-4-ether compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds. The present invention is also directed to uses of these pharmaceutical compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2014/019843, filed Mar. 3, 2014, whichclaims priority under 35 U.S.C. §119(e) from U.S. Ser. No. 61/774,710,filed Mar. 8, 2013.

BACKGROUND OF THE INVENTION

The orexins (hypocretins) comprise two neuropeptides produced in thehypothalamus: the orexin A (OX-A) (a 33 amino acid peptide) and theorexin B (OX-B) (a 28 amino acid peptide) (Sakurai T. et al., Cell,1998, 92, 573-585). Orexins are found to stimulate food consumption inrats suggesting a physiological role for these peptides as mediators inthe central feedback mechanism that regulates feeding behavior (SakuraiT. et al., Cell, 1998, 92, 573-585). Orexins regulate states of sleepand wakefulness opening potentially novel therapeutic approaches fornarcoleptic or insomniac patients (Chemelli R. M. et al., Cell, 1999,98, 437-451). Orexins have also been indicated as playing a role inarousal, reward, learning and memory (Harris, et al., Trends Neurosci.,2006, 29 (10), 571-577). Two orexin receptors have been cloned andcharacterized in mammals. They belong to the super family of G-proteincoupled receptors (Sakurai T. et al., Cell, 1998, 92, 573-585): theorexin-1 receptor (OX or OX1R) is selective for OX-A and the orexin-2receptor (OX2 or OX2R) is capable to bind OX-A as well as OX-B. Thephysiological actions in which orexins are presumed to participate arethought to be expressed via one or both of OX1 receptor and OX2 receptoras the two subtypes of orexin receptors.

SUMMARY OF THE INVENTION

The present invention is directed to 2-pyridyloxy-4-ether compoundswhich are antagonists of orexin receptors. The present invention is alsodirected to uses of the 2-pyridyloxy-4-ether compounds described hereinin the potential treatment or prevention of neurological and psychiatricdisorders and diseases in which orexin receptors are involved. Thepresent invention is also directed to pharmaceutical compositionscomprising these compounds. The present invention is also directed touses of these pharmaceutical compositions in the prevention or treatmentof such diseases in which orexin receptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   A is selected from the group consisting of phenyl, naphthyl and    heteroaryl;-   R^(1a), R^(1b) and R^(1c) are independently selected from the group    consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) —(C═O)_(m)—O_(n)—C₁₋₆ alkyl, where m is 0 or 1, n is 0 or 1        (wherein if m is 0 or n is 0, a bond is present) and where the        alkyl is unsubstituted or substituted with one or more        substituents selected from R⁴,    -   (5) —(C═O)_(m)—O_(n)—C₃₋₆ cycloalkyl, where the cycloalkyl is        unsubstituted or substituted with one or more substituents        selected from R⁴,    -   (6) —(C═O)_(m)—C₂₋₄ alkenyl, where the alkenyl is unsubstituted        or substituted with one or more substituents selected from R⁴,    -   (7) —(C═O)_(m)—C₂₋₄ alkynyl, where the alkynyl is unsubstituted        or substituted with one or more substituents selected from R⁴,    -   (8) —(C═O)_(m)—O_(n)-phenyl or —(C═O)_(m)—O_(n)-naphthyl, where        the phenyl or naphthyl is unsubstituted or substituted with one        or more substituents selected from R⁴,    -   (9) —(C═O)_(m)—O_(n)-heterocycle, where the heterocycle is        unsubstituted or substituted with one or more substituents        selected from R⁴,    -   (10) —(C═O)_(m)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently        selected from the group consisting of:        -   (a) hydrogen,        -   (b) C₁₋₆ alkyl, which is unsubstituted or substituted with            R⁴,        -   (c) C₃₋₆ alkenyl, which is unsubstituted or substituted with            R⁴,        -   (d) C₃₋₆ alkynyl, which is unsubstituted or substituted with            R⁴,        -   (e) C₃₋₆ cycloalkyl which is unsubstituted or substituted            with R⁴,        -   (f) phenyl, which is unsubstituted or substituted with R⁴,            and        -   (g) heterocycle, which is unsubstituted or substituted with            R⁴,    -   (11) —S(O)₂—NR¹⁰R¹¹,    -   (12) —S(O)_(q)—R¹², where q is 0, 1 or 2 and where R¹² is        selected from the definitions of R¹⁰ and R¹¹,    -   (13) —CO₂H,    -   (14) —CN, and    -   (15) —NO₂;-   R³ is selected from C₁₋₆ alkyl and C₃₋₆ cycloalkyl, which is    unsubstituted or substituted with one or more substituents selected    from R⁴;-   R⁴ is selected from the group consisting of:    -   (1) hydroxyl,    -   (2) halogen,    -   (3) C₁₋₆ alkyl,    -   (4) —C₃₋₆cycloalkyl,    -   (5) —O—C₁₋₆ alkyl,    -   (6) —O(C═O)—C₁₋₆ alkyl,    -   (7) —NH₂,    -   (7) —NH—C₁₋₆alkyl,    -   (8) —NO₂,    -   (9) phenyl,    -   (10) heterocycle,    -   (11) —CO₂H, and    -   (12) —CN;-   R⁵ is selected from the group consisting of:    -   (1) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen or phenyl,    -   (2) C₃₋₆cycloalkyl, which is unsubstituted or substituted with        C₁₋₆ alkyl, halogen or phenyl, and    -   (3) phenyl, which is unsubstituted or substituted with C₁₋₆        alkyl, halogen or phenyl;-   R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₂₋₆ alkenyl,    -   (4) C₃₋₆ cycloalkyl,    -   (5) —(C═O)—H, and    -   (6) —(C═O)—C₁₋₆ alkyl;        or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa′:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa″:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein R^(1a), R^(1b), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb′:

wherein R^(1a), R^(1b), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb″:

wherein R^(1a), R^(1b), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc′:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc″:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaId:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaId′:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaId″:

wherein R^(1a), R^(1b), R^(1c), R³ and R⁵ are defined herein; or apharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIe:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIe′:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIe″:

wherein R^(1a), R³ and R⁵ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds wherein A isselected from phenyl, pyridyl, thiophenyl, thiazolyl, isothiazolyl, andpyrazolyl. An embodiment of the present invention includes compoundswherein A is phenyl. An embodiment of the present invention includescompounds wherein A is pyridyl. An embodiment of the present inventionincludes compounds wherein A is thiophenyl. An embodiment of the presentinvention includes compounds wherein A is thiazolyl. An embodiment ofthe present invention includes compounds wherein A is isothiazolyl. Anembodiment of the present invention includes compounds wherein A ispyrazolyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) heteroaryl, wherein heteroaryl is selected from imidazolyl,        indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,        and triazolyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆alkyl or —NO₂,    -   (7) phenyl, which is unsubstituted or substituted with halogen,        hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl or —NO₂,    -   (8) —O-phenyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆alkyl, —O—C₁₋₆ alkyl or —NO₂,    -   (9) —CN, and    -   (10) —NH—C₁₋₆ alkyl, or —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), which is        unsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,        and —O—C₁₋₆alkyl.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) hydroxyl,    -   (4) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (5) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (6) —CN, and    -   (7) heteroaryl, wherein heteroaryl is selected from imidazolyl,        indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,        and triazolyl, which is unsubstituted or substituted with        halogen, hydroxyl, C₁₋₆ alkyl, —O—C₁₋₆ alkyl or —NO₂.

An embodiment of the present invention includes compounds whereinR^(1a), R^(1b) and R^(1c) are independently selected from the groupconsisting of:

-   -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen,    -   (4) —O—C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen,    -   (5) —CN, and    -   (6) heteroaryl, wherein heteroaryl is selected from imidazolyl,        indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,        and triazolyl.

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, and R^(1a) and R^(1b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) bromo,    -   (5) methyl,    -   (6) ethyl,    -   (7) methoxy,    -   (8) trifluoromethyl, and    -   (9) heteroaryl, wherein heteroaryl is selected from imidazolyl,        indolyl, oxazolyl, pyridyl, pyrrolyl, pyrimidinyl, tetrazolyl,        and triazolyl,

An embodiment of the present invention includes compounds wherein R^(1c)is hydrogen, and R^(1a) and R^(1b) are independently selected from thegroup consisting of:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) methyl,    -   (5) methoxy,    -   (6) tetrazolyl, and    -   (7) triazolyl.

An embodiment of the present invention includes compounds wherein R³ isC₁₋₆ alkyl. An embodiment of the present invention includes compoundswherein R³ is C₃₋₆ cycloalkyl. An embodiment of the present inventionincludes compounds wherein R³ is methyl or ethyl. An embodiment of thepresent invention includes compounds wherein R³ is methyl. An embodimentof the present invention includes compounds wherein R³ is (R)-methyl.

An embodiment of the present invention includes compounds wherein R⁵ isselected from the group consisting of:

-   -   (1) C₁₋₆ alkyl, which is unsubstituted or substituted with        halogen or phenyl,    -   (2) C₃₋₆ cycloalkyl, which is unsubstituted or substituted with        C₁₋₆ alkyl or halogen, and    -   (3) phenyl.

An embodiment of the present invention includes compounds wherein R⁵ isselected from the group consisting of: methyl, fluoro-methyl,difluoro-methyl, ethyl, fluoroethyl, isopropyl, cyclopropyl, butyl,2,2-difluoro-ethyl, phenyl, and benzyl.

An embodiment of the present invention includes compounds wherein R⁵ ismethyl. An embodiment of the present invention includes compoundswherein R⁵ is ethyl. An embodiment of the present invention includescompounds wherein R⁵ is isopropyl.

An embodiment of the present invention includes compounds wherein R⁶ isselected from the group consisting of:

-   -   (1) hydrogen,    -   (2) fluoro,    -   (3) chloro,    -   (4) bromo,    -   (5) methyl,    -   (6) ethenyl,    -   (7) —(C═O)—H, and    -   (8) —(C═O)—CH₃.

An embodiment of the present invention includes compounds wherein R⁶ ishydrogen.

Certain embodiments of the present invention include a compound which isselected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without specificstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆ alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₆ alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents. The term “heterocycle” as used herein includes bothunsaturated and saturated heterocyclic moieties, wherein the unsaturatedheterocyclic moieties (i.e. “heteroaryl”) include benzoimidazolyl,benzimidazolonyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzothiazolyl, benzotriazolyl, benzothiophenyl, benzoxazepin,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl,indolinyl, indolyl, dihydroindolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, and N-oxides thereof, andwherein the saturated heterocyclic moieties include azetidinyl,1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,thiomorpholinyl, and tetrahydrothienyl, and N-oxides thereof.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes suitable for inclusion inthe compounds of the invention include isotopes of hydrogen such as ²Hand ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N,oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as ³²P, sulfur such as³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorinesuch as ³⁶Cl. Certain isotopically-labelled compounds of Formula I, forexample those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labelled compoundsof Formula I can generally be prepared by conventional techniques knownto those skilled in the art or by processes analogous to those describedin the accompanying Examples using appropriate isotopically-labelledreagents in place of the non-labelled reagent previously employed.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particular embodiments includethe ammonium, calcium, magnesium, potassium, and sodium salts. Salts inthe solid form may exist in more than one crystal structure, and mayalso be in the form of hydrates. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particular embodiments include the citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

The subject compounds are useful in a method of antagonizing orexinreceptor activity in a patient such as a mammal in need of suchinhibition comprising the administration of an effective amount of thecompound. The present invention is directed to the use of the compoundsdisclosed herein as antagonists of orexin receptor activity. In additionto primates, especially humans, a variety of other mammals may betreated according to the method of the present invention. The presentinvention is directed to a compound of the present invention or apharmaceutically acceptable salt thereof that could be useful inmedicine. The present invention may further be directed to a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the manufacture of a medicament for antagonizing orexinreceptor activity or treating the disorders and diseases noted herein inhumans and animals.

The subject treated in the present methods is generally a mammal, suchas a human being, male or female. The term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by the researcher, veterinarian, medical doctor or otherclinician. It is recognized that one skilled in the art may affect theneurological and psychiatric disorders by treating a patient presentlyafflicted with the disorders or by prophylactically treating a patientafflicted with the disorders with an effective amount of the compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a patient who is predisposed to such disease ordisorder. The terms “administration of” and or “administering a”compound should be understood to mean providing a compound of theinvention or a prodrug of a compound of the invention to the individualin need thereof.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The utility of the compounds in accordance with the present invention asorexin receptor OX1R and/or OX2R antagonists may be readily determinedwithout undue experimentation by methodology well known in the art,including the “FLIPR Ca²⁺ Flux Assay” (Okumura et al., Biochem. Biophys.Res. Comm. 280:976-981, 2001). In a typical experiment the OX1 and OX2receptor antagonistic activity of the compounds of the present inventionwas determined in accordance with the following experimental method. Forintracellular calcium measurements, Chinese hamster ovary (CHO) cellsexpressing the rat orexin-1 receptor or the human orexin-2 receptor, aregrown in Iscove's modified DMEM containing 2 mM L-glutamine, 0.5 g/mlG418, 1% hypoxanthine-thymidine supplement, 100 U/ml penicillin, 100μg/ml streptomycin and 10% heat-inactivated fetal calf serum (FCS). Thecells are seeded at 20,000 cells/well into Becton-Dickinson black384-well clear bottom sterile plates coated with poly-D-lysine. Allreagents were from GIBCO-Invitrogen Corp. The seeded plates areincubated overnight at 37° C. and 5% CO2. Ala-6,12 human orexin-A as theagonist is prepared as a 1 mM stock solution in 1% bovine serum albumin(BSA) and diluted in assay buffer (HBSS containing 20 mM HEPES, 0.1% BSAand 2.5 mM probenecid, pH7.4) for use in the assay at a finalconcentration of 70 pM. Test compounds are prepared as 10 mM stocksolution in DMSO, then diluted in 384-well plates, first in DMSO, thenassay buffer. On the day of the assay, cells are washed 3 times with 100μl assay buffer and then incubated for 60 min (37° C., 5% CO2) in 60 μlassay buffer containing 1 μM Fluo-4AM ester, 0.02% pluronic acid, and 1%BSA. The dye loading solution is then aspirated and cells are washed 3times with 100 μl assay buffer. 30 μl of that same buffer is left ineach well. Within the Fluorescent Imaging Plate Reader (FLIPR, MolecularDevices), test compounds are added to the plate in a volume of 25 μl,incubated for 5 min and finally 25 μl of agonist is added. Fluorescenceis measured for each well at 1 second intervals for 5 minutes and theheight of each fluorescence peak is compared to the height of thefluorescence peak induced by 70 pM Ala-6,12 orexin-A with buffer inplace of antagonist. For each antagonist, IC50 value (the concentrationof compound needed to inhibit 50% of the agonist response) isdetermined. Alternatively, compound potency can be assessed by aradioligand binding assay (described in Bergman et. al. Bioorg. Med.Chem. Lett. 2008, 18, 1425-1430) in which the inhibition constant(K_(i)) is determined in membranes prepared from CHO cells expressingeither the OX1 or OX2 receptor. The intrinsic orexin receptor antagonistactivity of a compound which may be used in the present invention may bedetermined by these assays.

All of the final compounds of the following examples had activity inantagonizing the human orexin-2 receptor in the aforementioned assayswith an IC₅₀ of about 0.1 nM to 100 nM. All of the final compounds ofthe following examples had activity in the radioligand binding assaywith a Ki of about 0.1 nM to 100 nM against the orexin-2 receptor. Allof the final compounds of the following examples had activity in theFLIPR assay with an IC50 of about 0.1 nM to 100 nM against the orexin-2receptor. Additional data is provided in the following Examples. Such aresult is indicative of the intrinsic activity of the compounds in useas antagonists of orexin-1 receptor and/or the orexin-2 receptor. Ingeneral, one of ordinary skill in the art would appreciate that asubstance is considered to effectively antagonize the orexin receptor ifit has an IC50 of less than about 50 μM, preferably less than about 100nM. With respect to other piperidine compounds such as those disclosedin WO 2010/048012, it would be desirable that the present compoundsexhibit unexpected properties, such as increased selectivity at theorexin-2 receptor relative to the orexin-1 receptor. For example,relative to 2-pyridyloxy compounds of WO2010/048012 that do not possessa 2-pyridyloxy-4-ether substituent, the compounds of the examplespossess greater selectivity for the orexin-2 receptor than for theorexin-1 receptor.

The orexin receptors have been implicated in a wide range of biologicalfunctions. This has suggested a potential role for these receptors in avariety of disease processes in humans or other species. The compoundsof the present invention could therefore potentially have utility intreating, preventing, ameliorating, controlling or reducing the risk ofa variety of neurological and psychiatric disorders associated withorexin receptors, including one or more of the following conditions ordiseases: sleep disorders, sleep disturbances, including enhancing sleepquality, improving sleep quality, increasing sleep efficiency,augmenting sleep maintenance; increasing the value which is calculatedfrom the time that a subject sleeps divided by the time that a subjectis attempting to sleep; improving sleep initiation; decreasing sleeplatency or onset (the time it takes to fall asleep); decreasingdifficulties in falling asleep; increasing sleep continuity; decreasingthe number of awakenings during sleep; decreasing intermittent wakingsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; decreasing nocturnalarousals, especially early morning awakenings; increasing daytimealertness; reducing daytime drowsiness; treating or reducing excessivedaytime sleepiness; increasing satisfaction with the intensity of sleep;increasing sleep maintenance; idiopathic insomnia; sleep problems;insomnia, hypersomnia, idiopathic hypersomnia, repeatabilityhypersomnia, intrinsic hypersomnia, narcolepsy, interrupted sleep, sleepapnea, wakefulness, nocturnal myoclonus, REM sleep interruptions,jet-lag, shift workers' sleep disturbances, dyssomnias, night terror,insomnias associated with depression, emotional/mood disorders,Alzheimer's disease or cognitive impairment, as well as sleep walkingand enuresis, and sleep disorders which accompany aging; Alzheimer'ssundowning; conditions associated with circadian rhythmicity as well asmental and physical disorders associated with travel across time zonesand with rotating shift-work schedules, conditions due to drugs whichcause reductions in REM sleep as a side effect; fibromyalgia; syndromeswhich are manifested by non-restorative sleep and muscle pain or sleepapnea which is associated with respiratory disturbances during sleep;conditions which result from a diminished quality of sleep; increasinglearning; augmenting memory; increasing retention of memory; eatingdisorders associated with excessive food intake and complicationsassociated therewith, compulsive eating disorders, obesity (due to anycause, whether genetic or environmental), obesity-related disordersovereating, anorexia, bulimia, cachexia, dysregulated appetite control,hypertension, diabetes, elevated plasma insulin concentrations andinsulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast,prostate and colon cancer, osteoarthritis, obstructive sleep apnea,cholelithiasis, gallstones, heart disease, lung disease, abnormal heartrhythms and arrythmias, myocardial infarction, congestive heart failure,coronary heart disease, acute and congestive heart failure; hypotension;hypertension; urinary retention; osteoporosis; angina pectoris;myocardinal infarction; ischemic or haemorrhagic stroke; subarachnoidhaemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronicrenal failure; renal disease; impaired glucose tolerance; sudden death,polycystic ovary disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia, metabolic syndrome, also known as syndrome X,insulin resistance syndrome, reproductive hormone abnormalities, sexualand reproductive dysfunction, such as impaired fertility, infertility,hypogonadism in males and hirsutism in females, fetal defects associatedwith maternal obesity, gastrointestinal motility disorders, intestinalmotility dyskinesias, obesity-related gastro-esophageal reflux,hypothalmic diseases, hypophysis diseases, respiratory disorders, suchas obesity-hypoventilation syndrome (Pickwickian syndrome),breathlessness, cardiovascular disorders, inflammation, such as systemicinflammation of the vasculature, arteriosclerosis, hypercholesterolemia,hyperuricaemia, lower back pain, gallbladder disease, gout, kidneycancer, increased anesthetic risk, reducing the risk of secondaryoutcomes of obesity, such as reducing the risk of left ventricularhypertrophy; diseases or disorders where abnormal oscillatory activityoccurs in the brain, including depression, migraine, neuropathic pain,Parkinson's disease, psychosis and schizophrenia, as well as diseases ordisorders where there is abnormal coupling of activity, particularlythrough the thalamus; enhancing cognitive function, including cognitivedysfunctions that comprise deficits in all types of attention, learningand memory functions occurring transiently or chronically in the normal,healthy, young, adult or aging population, and also occurringtransiently or chronically in psychiatric, neurologic, cardiovascularand immune disorders; enhancing memory; increasing memory retention;increasing immune response; increasing immune function; hot flashes;night sweats; extending life span; schizophrenia; muscle-relateddisorders that are controlled by the excitation/relaxation rhythmsimposed by the neural system such as cardiac rhythm and other disordersof the cardiovascular system; conditions related to proliferation ofcells such as vasodilation or vasorestriction and blood pressure;cancer; cardiac arrhythmia; hypertension; congestive heart failure;conditions of the genital/urinary system; disorders of sexual functionand fertility; adequacy of renal function; responsivity to anesthetics;mood disorders, such as depression or more particularly depressivedisorders, for example, single episodic or recurrent major depressivedisorders and dysthymic disorders, or bipolar disorders, for example,bipolar I disorder, bipolar II disorder and cyclothymic disorder, mooddisorders due to a general medical condition, and substance-induced mooddisorders; affective neurosis; depressive neurosis; anxiety neurosis;anxiety disorders including acute stress disorder, agoraphobia,generalized anxiety disorder, obsessive-compulsive disorder, panicattack, panic disorder, post-traumatic stress disorder, separationanxiety disorder, social phobia, specific phobia, substance-inducedanxiety disorder and anxiety due to a general medical condition; acuteneurological and psychiatric disorders such as cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, ischemicstroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage; Huntington'sChorea; Huntington's disease and Tourette syndrome; Cushing'ssyndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia;hypophysis tumor/adenoma; hypothalamic diseases; inflammatory boweldisease; gastric diskinesia; gastric ulcers; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; adrenohypophysishypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;Kallman's syndrome (anosmia, hyposmia); functional or psychogenicamenorrhea; hypopituitarism; hypothalamic hypothyroidism;hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia;hypothalamic disorders of growth hormone deficiency; idiopathic growthdeficiency; dwarfism; gigantism; acromegaly; amyotrophic lateralsclerosis; multiple sclerosis; ocular damage; retinopathy; cognitivedisorders; idiopathic and drug-induced Parkinson's disease; muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, seizure disorders, absence seisures,complex partial and generalized seizures; Lennox-Gastaut syndrome;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, trauma, vascular problems or stroke, HIV disease,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-inducedpsychotic disorder; dissociateive disorders including multiplepersonality syndromes and psychogenic amnesias; substance-relateddisorders, substance use, substance abuse, substance seeking, substancereinstatement, all types of psychological and physical addictions andaddictive behaviors, reward-related behaviors (includingsubstance-induced delirium, persisting dementia, persisting amnesticdisorder, psychotic disorder or anxiety disorder; tolerance, addictivefeeding, addictive feeding behaviors, binge/purge feeding behaviors,dependence, withdrawal or relapse from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);appetite, taste, eating or drinking disorders; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, parkinsonism-ALS dementia complex and basal gangliacalcification), chronic fatigue syndrome, fatigue, including Parkinson'sfatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorderor a circadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); neurodegenerativedisorders including nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders;attention deficit/hyperactivity disorder (ADHD); conduct disorder;migraine (including migraine headache); headache; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); asthma; cancer; conditions associated withvisceral pain such as irritable bowel syndrome, and angina; eatingdisorders; urinary incontinence; substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.); psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache and other diseases related togeneral orexin system dysfunction.

Thus, in certain embodiments the present invention may provide methodsfor: enhancing the quality of sleep; augmenting sleep maintenance;increasing REM sleep; increasing stage 2 sleep; decreasing fragmentationof sleep patterns; treating insomnia and all types of sleep disorders;treating or controlling sleep disturbances associated with diseases suchas neurological disorders including neuropathic pain and restless legsyndrome; treating or controlling addiction disorders; treating orcontrolling psychoactive substance use and abuse; enhancing cognition;increasing memory retention; treating or controlling obesity; treatingor controlling diabetes and appetite, taste, eating, or drinkingdisorders; treating or controlling hypothalamic diseases; treating orcontrolling depression; treating, controlling, ameliorating or reducingthe risk of epilepsy, including absence epilepsy; treating orcontrolling pain, including neuropathic pain; treating or controllingParkinson's disease; treating or controlling psychosis; treating orcontrolling dysthymic, mood, psychotic and anxiety disorders; treatingor controlling depression, including major depression and majordepression disorder; treating or controlling bipolar disorder; ortreating, controlling, ameliorating or reducing the risk ofschizophrenia, in a mammalian patient in need thereof which comprisesadministering to the patient a therapeutically effective amount of acompound of the present invention.

The subject compounds could further be of potential use in a method forthe prevention, treatment, control, amelioration, or reduction of riskof the diseases, disorders and conditions noted herein. The dosage ofactive ingredient in the compositions of this invention may be varied,however, it is necessary that the amount of the active ingredient besuch that a suitable dosage form is obtained. The active ingredient maybe administered to patients (animals and human) in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from patient to patient depending upon the nature and severityof disease, the patient's weight, special diets then being followed by apatient, concurrent medication, and other factors which those skilled inthe art will recognize. Generally, dosage levels of between 0.0001 to 10mg/kg. of body weight daily are administered to the patient, e.g.,humans and elderly humans, to obtain effective antagonism of orexinreceptors. The dosage range will generally be about 0.5 mg to 1.0 g. perpatient per day which may be administered in single or multiple doses.In one embodiment, the dosage range will be about 0.5 mg to 500 mg perpatient per day; in another embodiment about 0.5 mg to 200 mg perpatient per day; and in yet another embodiment about 5 mg to 50 mg perpatient per day. Pharmaceutical compositions of the present inventionmay be provided in a solid dosage formulation such as comprising about0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mgactive ingredient. The pharmaceutical composition may be provided in asolid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30mg, 50 mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 Hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includetherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, such as about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered incombination with other compounds which are known in the art to be usefulfor enhancing sleep quality and preventing and treating sleep disordersand sleep disturbances, including e.g., sedatives, hypnotics,anxiolytics, antipsychotics, antianxiety agents, antihistamines,benzodiazepines, barbiturates, cyclopyrrolones, GABA agonists, 5HT-2antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists,histamine antagonists including histamine H3 antagonists, histamine H3inverse agonists, imidazopyridines, minor tranquilizers, melatoninagonists and antagonists, melatonergic agents, other orexin antagonists,orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam,gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine,indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline,MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate,methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone,NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine,tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam,trepipam, tricetamide, triclofos, trifluoperazine, trimetozine,trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone,zolpidem, and salts thereof, and combinations thereof, and the like, orthe compound of the present invention may be administered in conjunctionwith the use of physical methods such as with light therapy orelectrical stimulation.

In another embodiment, the subject compound may be employed incombination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,including, but are not limited to: insulin sensitizers including (i)PPARγ antagonists such as glitazones (e.g. ciglitazone; darglitazone;englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone;troglitazone; tularik; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641,and LY-300512, and the like); (iii) biguanides such as metformin andphenformin; (b) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (73-7)(insulintropin); and GLP-1 (7-36)-NH2); (c) sulfonylureas, such asacetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide;glyburide; glimepiride; gliclazide; glipentide; gliquidone; glisolamide;tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such asacarbose, adiposine; camiglibose; emiglitate; miglitol; voglibose;pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945; and MOR 14,and the like; (e) cholesterol lowering agents such as (i) HMG-CoAreductase inhibitors (atorvastatin, itavastatin, fluvastatin,lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, andother statins), (ii) bile acid absorbers/sequestrants, such ascholestyramine, colestipol, dialkylaminoalkyl derivatives of across-linked dextran; Colestid®; LoCholest®, and the like, (ii)nicotinyl alcohol, nicotinic acid or a salt thereof, (iii)proliferator-activater receptor α agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate),(iv) inhibitors of cholesterol absorption such as stanol esters,beta-sitosterol, sterol glycosides such as tiqueside; and azetidinonessuch as ezetimibe, and the like, and (acyl CoA:cholesterolacyltransferase (ACAT)) inhibitors such as avasimibe, and melinamide,(v) anti-oxidants, such as probucol, (vi) vitamin E, and (vii)thyromimetics; (f) PPARα agonists such as beclofibrate, benzafibrate,ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; andother fabric acid derivatives, such as Atromid®, Lopid® and Tricor®, andthe like, and PPARα agonists as described in WO 97/36579; (g) PPARδagonists, such as those disclosed in WO97/28149; (h) PPAR α/δ agonists,such as muraglitazar, and the compounds disclosed in U.S. Pat. No.6,414,002; (i) anti-obesity agents, such as (1) growth hormonesecretagogues, growth hormone secretagogue receptoragonists/antagonists, such as NN703, hexarelin, MK-0677, SM-130686,CP-424,391, L-692,429, and L-163,255, and such as those disclosed inU.S. Pat. Nos. 5,536,716, and 6,358,951, U.S. Patent Application Nos.2002/049196 and 2002/022637, and PCT Application Nos. WO 01/56592 and WO02/32888; (2) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; (3)cannabinoid receptor ligands, such as cannabinoid CB₁ receptorantagonists or inverse agonists, such as rimonabant, taranabant,AMT-251, and SR-14778 and SR 141716A (Sanofi Synthelabo), SLV-319(Solvay), BAY 65-2520 (Bayer) and those disclosed in U.S. Pat. Nos.5,532,237, 4,973,587, 5,013,837, 5,081,122, 5,112,820, 5,292,736,5,624,941, 6,028,084, PCT Application Nos. WO 96/33159, WO 98/33765,WO98/43636, WO98/43635, WO 01/09120, WO98/31227, WO98/41519, WO98/37061,WO00/10967, WO00/10968, WO97/29079, WO99/02499, WO 01/58869, WO01/64632, WO 01/64633, WO 01/64634, WO02/076949, WO 03/007887, WO04/048317, and WO 05/000809; (4) anti-obesity serotonergic agents, suchas fenfluramine, dexfenfluramine, phentermine, and sibutramine; (5)β3-adrenoreceptor agonists, such as AD9677/TAK677 (Dainippon/Takeda),CL-316,243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A,CGP12177A, BTA-243, Trecadrine, Zeneca D7114, SR 59119A; (6) pancreaticlipase inhibitors, such as orlistat (Xenical®), Triton WR1339, RHC80267,lipstatin, tetrahydrolipstatin, teasaponin, diethylumbelliferylphosphate, and those disclosed in PCT Application No. WO 01/77094; (7)neuropeptide Y1 antagonists, such as BIBP3226, J-115814, BIBO 3304,LY-357897, CP-671906, GI-264879A, and those disclosed in U.S. Pat. No.6,001,836, and PCT Patent Publication Nos. WO 96/14307, WO 01/23387, WO99/51600, WO 01/85690, WO 01/85098, WO 01/85173, and WO 01/89528; (8)neuropeptide Y5 antagonists, such as GW-569180A, GW-594884A, GW-587081X,GW-548118X, FR226928, FR 240662, FR252384, 1229U91, GI-264879A,CGP71683A, LY-377897, PD-160170, SR-120562A, SR-120819A and JCF-104, andthose disclosed in U.S. Pat. Nos. 6,057,335; 6,043,246; 6,140,354;6,166,038; 6,180,653; 6,191,160; 6,313,298; 6,335,345; 6,337,332;6,326,375; 6,329,395; 6,340,683; 6,388,077; 6,462,053; 6,649,624; and6,723,847, European Patent Nos. EP-01010691, and EP-01044970; and PCTInternational Patent Publication Nos. WO 97/19682, WO 97/20820, WO97/20821, WO 97/20822, WO 97/20823, WO 98/24768; WO 98/25907; WO98/25908; WO 98/27063, WO 98/47505; WO 98/40356; WO 99/15516; WO99/27965; WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO01/14376; WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO01/62738, WO 01/09120, WO 02/22592, WO 0248152, and WO 02/49648; WO02/094825; WO 03/014083; WO 03/10191; WO 03/092889; WO 04/002986; and WO04/031175; (9) melanin-concentrating hormone (MCH) receptor antagonists,such as those disclosed in WO 01/21577 and WO 01/21169; (10)melanin-concentrating hormone 1 receptor (MCH1R) antagonists, such asT-226296 (Takeda), and those disclosed in PCT Patent Application Nos. WO01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO03/004027; (11) melanin-concentrating hormone 2 receptor (MCH2R)agonist/antagonists; (12) orexin receptor antagonists, such asSB-334867-A, and those disclosed in patent publications herein; (13)serotonin reuptake inhibitors such as fluoxetine, paroxetine, andsertraline; (14) melanocortin agonists, such as Melanotan II; (15) Mc4r(melanocortin 4 receptor) agonists, such as CHIR86036 (Chiron),ME-10142, and ME-10145 (Melacure), CHIR86036 (Chiron); PT-141, and PT-14(Palatin); (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C)agonists, such as BVT933, DPCA37215, WAY161503, R-1065, and thosedisclosed in U.S. Pat. No. 3,914,250, and PCT Application Nos. WO02/36596, WO 02/48124, WO 02/10169, WO 01/66548, WO 02/44152, WO02/51844, WO 02/40456, and WO 02/40457; (18) galanin antagonists; (19)CCK agonists; (20) CCK-A (cholecystokinin-A) agonists, such as AR-R15849, GI 181771, JMV-180, A-71378, A-71623 and SR14613, and thosediscribed in U.S. Pat. No. 5,739,106; (21) GLP-1 agonists; (22)corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3)modulators; (24) histamine receptor-3 (H3) antagonists/inverse agonists,such as hioperamide, 3-(1H-imidazol-4-yl)propyl N-(4-pentenyl)carbamate,clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech), andO-[3-(1H-imidazol-4-yl)propanol]-carbamates; (25) β-hydroxy steroiddehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase)inhibitors, such as theophylline, pentoxifylline, zaprinast, sildenafil,amrinone, milrinone, cilostamide, rolipram, and cilomilast; (27)phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine)transport inhibitors, such as GW 320659, despiramine, talsupram, andnomifensine; (29) ghrelin receptor antagonists, such as those disclosedin PCT Application Nos. WO 01/87335, and WO 02/08250; (30) leptin,including recombinant human leptin (PEG-OB, Hoffman La Roche) andrecombinant methionyl human leptin (Amgen); (31) leptin derivatives;(32) BRS3 (bombesin receptor subtype 3) agonists such as[D-Phe6,beta-Ala11,Phe13,Nle14]Bn(6-14) and[D-Phe6,Phe13]Bn(6-13)propylamide, and those compounds disclosed inPept. Sci. 2002 August; 8(8): 461-75); (33) CNTF (Ciliary neurotrophicfactors), such as GI-181771 (Glaxo-SmithKline), SR146131 (SanofiSynthelabo), butabindide, PD170,292, and PD 149164 (Pfizer); (34) CNTFderivatives, such as axokine (Regeneron); (35) monoamine reuptakeinhibitors, such as sibutramine; (36) UCP-1 (uncoupling protein-1), 2,or 3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), retinoic acid; (37) thyroid hormone β agonists, such asKB-2611 (KaroBioBMS); (38) FAS (fatty acid synthase) inhibitors, such asCerulenin and C75; (39) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) glucocorticoidantagonists; (43) acyl-estrogens, such as oleoyl-estrone, disclosed indel Mar-Grasa, M. et al., Obesity Research, 9:202-9 (2001); (44)dipeptidyl peptidase IV (DP-IV) inhibitors, such as isoleucinethiazolidide, valine pyrrolidide, NVP-DPP728, LAF237, P93/01, TSL 225,TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, sitagliptin;and the compounds disclosed in U.S. Pat. No. 6,699,871, WO 03/004498; WO03/004496; EP 1 258 476; WO 02/083128; WO 02/062764; WO 03/000250; WO03/002530; WO 03/002531; WO 03/002553; WO 03/002593; WO 03/000180; andWO 03/000181; (46) dicarboxylate transporter inhibitors; (47) glucosetransporter inhibitors; (48) phosphate transporter inhibitors; (49)Metformin (Glucophage®); (50) Topiramate (Topimax®); (50) peptide YY,PYY 3-36, peptide YY analogs, derivatives, and fragments such asBIM-43073D, BIM-43004C (Olitvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 (1999)); (51) Neuropeptide Y2 (NPY2) receptor agonists suchNPY3-36, N acetyl [Leu(28,31)] NPY 24-36, TASP-V, andcyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY; (52) Neuropeptide Y4 (NPY4)agonists such as pancreatic peptide (PP), and other Y4 agonists such as1229U91; (54) cyclooxygenase-2 inhibitors such as etoricoxib, celecoxib,valdecoxib, parecoxib, lumiracoxib, BMS347070, tiracoxib or JTE522,ABT963, CS502 and GW406381; (55) Neuropeptide Y1 (NPY1) antagonists suchas BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, GI-264879A; (56)Opioid antagonists such as nalmefene (Revex®), 3-methoxynaltrexone,naloxone, naltrexone; (57) 11β HSD-1 (11-beta hydroxy steroiddehydrogenase type 1) inhibitors such as BVT 3498, BVT 2733, and thosedisclosed in WO 01/90091, WO 01/90090, WO 01/90092, U.S. Pat. No.6,730,690 and US 2004-0133011; (58) aminorex; (59) amphechloral; (60)amphetamine; (61) benzphetamine; (62) chlorphentermine; (63)clobenzorex; (64) cloforex; (65) clominorex; (66) clortermine; (67)cyclexedrine; (68) dextroamphetamine; (69) diphemethoxidine, (70)N-ethylamphetamine; (71) fenbutrazate; (72) fenisorex; (73) fenproporex;(74) fludorex; (75) fluminorex; (76) furfurylmethylamphetamine; (77)levamfetamine; (78) levophacetoperane; (79) mefenorex; (80)metamfepramone; (81) methamphetamine; (82) norpseudoephedrine; (83)pentorex; (84) phendimetrazine; (85) phenmetrazine; (86) picilorex; (87)phytopharm 57; and (88) zonisamide., (89) neuromedin U and analogs orderivatives thereof, (90) oxyntomodulin and analogs or derivativesthereof, and (91) Neurokinin-1 receptor antagonists (NK-1 antagonists)such as the compounds disclosed in: U.S. Pat. Nos. 5,162,339, 5,232,929,5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, and5,637,699.

In another embodiment, the subject compound may be employed incombination with an anti-depressant or anti-anxiety agent, includingnorepinephrine reuptake inhibitors (including tertiary amine tricyclicsand secondary amine tricyclics), selective serotonin reuptake inhibitors(SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors ofmonoamine oxidase (RIMAs), serotonin and noradrenaline reuptakeinhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists,α-adrenoreceptor antagonists, neurokinin-1 receptor antagonists,atypical anti-depressants, benzodiazepines, 5-HT_(1A) agonists orantagonists, especially 5-HT_(1A) partial agonists, and corticotropinreleasing factor (CRF) antagonists. Specific agents include:amitriptyline, clomipramine, doxepin, imipramine and trimipramine;amoxapine, desipramine, maprotiline, nortriptyline and protriptyline;citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine andsertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline;moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone,trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam,chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam;buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceuticallyacceptable salts thereof.

In another embodiment, the subject compound may be employed incombination with anti-Alzheimer's agents; beta-secretase inhibitors;gamma-secretase inhibitors; growth hormone secretagogues; recombinantgrowth hormone; HMG-CoA reductase inhibitors; NSAID's includingibuprofen; vitamin E; anti-amyloid antibodies; CB-1 receptor antagonistsor CB-1 receptor inverse agonists; antibiotics such as doxycycline andrifampin; N-methyl-D-aspartate (NMDA) receptor antagonists, such asmemantine; cholinesterase inhibitors such as galantamine, rivastigmine,donepezil, and tacrine; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H₃ antagonists; AMPAagonists; PDE IV inhibitors; GABA_(A) inverse agonists; or neuronalnicotinic agonists.

In another embodiment, the subject compound may be employed incombination with sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, cyclopyrrolones, imidazopyridines,pyrazolopyrimidines, minor tranquilizers, melatonin agonists andantagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2antagonists, and the like, such as: adinazolam, allobarbital, alonimid,alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate,clorethate, clozapine, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam,ethchlorvynol, etomidate, fenobam, flunitrazepam, flurazepam,fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam,hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline,mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, reclazepam, roletamide, secobarbital,sertraline, suproclone, temazepam, thioridazine, tracazolate,tranylcypromaine, trazodone, triazolam, trepipam, tricetamide,triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam,venlafaxine, zaleplon, zolazepam, zolpidem, and salts thereof, andcombinations thereof, and the like, or the subject compound may beadministered in conjunction with the use of physical methods such aswith light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole.

In another embodiment, the subject compound may be employed incombination with acetophenazine, alentemol, benzhexol, bromocriptine,biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam,fenoldopam, fluphenazine, haloperidol, levodopa, levodopa withbenserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine,molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide,pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl,thioridazine, thiothixene or trifluoperazine.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone.

In another embodiment, the subject compound may be employed incombination with a nicotine agonist or a nicotine receptor partialagonist such as varenicline, opioid antagonists (e.g., naltrexone(including naltrexone depot), antabuse, and nalmefene), dopaminergicagents (e.g., apomorphine), ADD/ADHD agents (e.g., methylphenidatehydrochloride (e.g., Ritalin® and Concerta®), atomoxetine (e.g.,Strattera®), a monoamine oxidase inhibitor (MAOI), amphetamines (e.g.,Adderall®)) and anti-obesity agents, such as apo-B/MTP inhibitors,11Beta-hydroxy steroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors,peptide YY3-36 or analogs thereof, MCR-4 agonists, CCK-A agonists,monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergicreceptor agonists, dopamine receptor agonists, melanocyte-stimulatinghormone receptor analogs, 5-HT2c receptor agonists, melaninconcentrating hormone receptor antagonists, leptin, leptin analogs,leptin receptor agonists, galanin receptor antagonists, lipaseinhibitors, bombesin receptor agonists, neuropeptide-Y receptorantagonists (e.g., NPY Y5 receptor antagonists), thyromimetic agents,dehydroepiandrosterone or analogs thereof, glucocorticoid receptorantagonists, other orexin receptor antagonists, glucagon-like peptide-1receptor agonists, ciliary neurotrophic factors, human agouti-relatedprotein antagonists, ghrelin receptor antagonists, histamine 3 receptorantagonists or inverse agonists, and neuromedin U receptor agonists, andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an anoretic agent such as aminorex, amphechloral,amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex,clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; selectiveserotonin reuptake inhibitor (SSRI); halogenated amphetaminederivatives, including chlorphentermine, cloforex, clortermine,dexfenfluramine, fenfluramine, picilorex and sibutramine; andpharmaceutically acceptble salts thereof.

In another embodiment, the subject compound may be employed incombination with an opiate agonist, a lipoxygenase inhibitor, such as aninhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor, such as acyclooxygenase-2 inhibitor, an interleukin inhibitor, such as aninterleukin-1 inhibitor, an NMDA antagonist, an inhibitor of nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example with a compound such as acetaminophen, asprin,codiene, fentanyl, ibuprofen, indomethacin, ketorolac, morphine,naproxen, phenacetin, piroxicam, a steroidal analgesic, sufentanyl,sunlindac, tenidap, and the like. Similarly, the subject compound may beadministered with a pain reliever; a potentiator such as caffeine, anH2-antagonist, simethicone, aluminum or magnesium hydroxide; adecongestant such as phenylephrine, phenylpropanolamine, pseudophedrine,oxymetazoline, ephinephrine, naphazoline, xylometazoline,propylhexedrine, or levo-desoxy-ephedrine; an antiitussive such ascodeine, hydrocodone, caramiphen, carbetapentane, or dextramethorphan; adiuretic; and a sedating or non-sedating antihistamine.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention may beeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. The compounds of the present invention may alsobe administered in the form of suppositories for rectal administration.For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention may be employed.The compounds of the present invention may also be formulated foradministered by inhalation. The compounds of the present invention mayalso be administered by a transdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art (e.g. PCT PatentPublications WO2001/68609, WO2004/085403, WO2005/118548, WO2008/147518,WO2009/143033 and WO2010/048012) or as illustrated herein. The followingabbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert-butyl;Ar: aryl; Ph: phenyl; BINAP:2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Bn: benzyl; Ac: acetyl;Boc: tert-butyloxy carbonyl; BSA: bovine serum albumin; CbzCl:benzylchloroformate; CDI: carbonyl diimidazole; DCM: dichloromethane;DCE: dichloroethane; DEAD: diethylazodicarboxylate; DIPEA:N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO:dimethylsulfoxide; CH₂Cl₂: dichloromethane; EDC:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et₃N: triethylamine;EtOAc: ethyl acetate; EtOH: ethanol; HCl: hydrogen chloride; HOAt:1-hydroxy-7-aza-benzotriazole; HOBT: hydroxybenzotriazole hydrate; HPLC:high performance liquid chromatography; Hunig's base:N,N-diisopropylethylamine; MeOH: methanol; MgSO₄: magnesium sulfate;MTBE: methyl tert-butyl ether; NaHCO₃: sodium bicarbonate; NaOH: sodiumhydroxide; NMM: N-methylmorpholine; PtO₂: platinum oxide; PyClu:1-(chloro-1-pyrrolidinylmethylene)-pyrrolidinium hexafluorophosphate;rt: room temperature; SOCl₂: thionyl chloride; T3P:2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; THF:tetrahydrofuran; TFA: trifluoracetic acid; X-Phos:2-(dicyclohexyl-phosphino)-2′,4′,6′-triisopropylbiphenyl. The compoundsof the present invention can be prepared in a variety of fashions.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

EXAMPLE 1

4-Ethoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridineStep 1: ±Benzyl trans-5-hydroxy-2-methylpiperidine-1-carboxylate (1)

To a solution of 6-methylpyridin-3-ol (20.0 g, 0.183 mol) in MeOH (200mL) was added concentrated HCl (15.43 mL, 0.1850 mol) and PtO₂ (2.40 g,0.011 mol). The resulting mixture was heated to 70° C. at 50 PSIovernight. The reaction was filtered over solka-floc to remove the PtO₂and concentrated to a solid to provide ±trans-6-methylpiperidin-3-olhydrochloride. The crude solid was taken on without furtherpurification.

A mixture of ±trans-6-methylpiperidin-3-ol hydrochloride (14.0 g, 0.092mol) in CH₂Cl₂ (150 mL) was cooled at 0° C. Triethylamine (51.5 mL,0.369 mol) was added slowly. CbzCl (13.59 mL, 0.092 mol) was addeddropwise, keeping the temperature below 20° C. The reaction was allowedto warm overnight to room temperature. The reaction was quenched byaddition of water and diluted further with additional CH₂Cl₂. The layerswere separated and the organics were dried over MgSO₄ and concentrated.The crude material was purified by silica gel gradient chromatography(0-75% ethyl acetate in hexanes), providing the titled compound as anoil.

Step 2: Benzyl (2R,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate (2)

To a solution of oxalyl chloride (13.17 mL, 0.150 mol) in CH₂Cl₂ (250mL) at −78° C. was added DMSO (14.23 mL, 0.201 mol) dropwise. Thereaction was aged for 20 min at −78° C., then±trans-6-methylpiperidin-3-ol hydrochloride (25.0 g, 0.100 mol) wasadded dropwise over 10 min and aged for an additional 10 min before thetriethylamine (41.9 mL, 0.301 mol) was added dropwise over 5 min at −78°C. The reaction was warmed to room temperature, then quenched withaddition of half-saturated, aqueous NaHCO₃ and additional CH₂Cl₂. Thelayers were separated and the organics were dried with MgSO₄ andconcentrated. The crude material was purified by silica gel gradientchromatography (0-50% ethyl acetate in hexanes), providing ±benzyl2-methyl-5-oxopiperidine-1-carboxylate as a yellow oil.

To a solution of THF (200 mL) and MeOH (11 mL) was added lithiumborohydride (2 M, 89 mL, 0.18 mol). Some gas evolution and smallexotherm were observed. The reaction was aged at room temperature for 30min before being cooled to −10° C. with an acetone:ice bath. ±Benzyl2-methyl-5-oxopiperidine-1-carboxylate (22.0 g, 0.089 mol) was thenadded dropwise, keeping the temperature below −5° C. The reaction wasthen aged at −10° C. for 30 min. The reaction was quenched by addinghalf-saturated, aqueous NaHCO₃, then extracted with EtOAc. The layerswere separated and the organics dried with MgSO₄. The organics wereconcentrated to give ±benzyl-5-hydroxy-2-methylpiperidine-1-carboxylateas a crude, colorless oil. Chiral separation (SFC, IC 30×250 mm, 15%MeOH/CO₂, 70 ml/min, 115 mg/ml in MeOH) of the crude±benzyl-5-hydroxy-2-methylpiperidine-1-carboxylate provided the titledcompound as enantiopure material.

Step 3: Benzyl(2R,5R)-2-methyl-5-{[(4-nitrophenyl)carbonyl]oxy}piperidine-1-carboxylate(3)

To a THF (909 ml) solution of benzyl(2R,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate (34 g, 136 mmol),4-(dimethylamino) phenyldiphenylphosphine (58.3 g, 191 mmol), and4-nitrobenzoic acid (29.6 g, 177 mmol) was added, under N₂, DEAD (30.0ml, 191 mmol) dropwise at −15 to −25° C. over 20 min. The reaction wasallowed to warm to RT overnight. The reaction was concentrated in vacuo,removing most THF, then diluted with Et₂O (500 mL). The mixture wascooled at 0° C. and washed with 1 N HCl (5×200 mL). The combined aqueousphases were back-extracted twice with Et₂O. The combined organic phaseswere subsequently washed twice more with 1 N HCl. The organics weredried over MgSO₄, filtered, and concentrated. The crude material waspurified by silica gel gradient chromatography (0-40% ethyl acetate inhexanes), providing the titled compound as a light yellow oil whichslowly solidified. LRMS m/z (M+H) 399.3 found, 399.1 required.

Step 4: Benzyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (4)

To a solution of benzyl(2R,5R)-2-methyl-5-{[(4-nitrophenyl)carbonyl]oxy}piperidine-1-carboxylate(54.3 g, 136 mmol) in THF (850 mL) and MeOH (138 mL) was added 1 N NaOH(204 mL) and water (30 mL). The solution was stirred overnight, thenconcentrated in vacuo. The residue was diluted with minimal brine andwater and extracted twice with EtOAc. The organics were washed withbrine, dried over MgSO₄, filtered, and concentrated to give the titledcompound as a crude, orange-yellow oil which was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 7.28-7.36 (m, 5H), 5.14 (d,J=3.5 Hz, 2H), 4.50 (t, J=6.8 Hz), 1H), 4.09 (d, J=8.8 Hz, 1H), 3.94 (s,1H), 3.09 (dd, J=14.3, 1.9 Hz, 1H), 2.06-2.15 (m, 1H), 1.96 (br s, 1H),1.75-1.83 (m, 1H), 1.66-1.72 (m, 1H), 1.24-1.32 (m, 2H), 1.16 (d, J=7.0Hz, 2H) ppm. LRMS m/z (M+H) 250.1 found, 250.1 required.

Step 5: (3R,6R)-6-Methylpiperidin-3-ol (5)

A solution of benzyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate(11.5 g, 46.1 mmol), and palladium (10 wt % on activated carbon, 3.68 g)in degassed EtOH (300 mL) was stirred for 3 nights under an atmosphereof hydrogen gas. The degassed mixture was then filtered over celite,washing with EtOH. The filtrate was concentrated to give the titledcompound as a crude, white solid which was used without furtherpurification. LRMS m/z (M+H) 116.1 found, 116.1 required.

Step 6:(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-hydroxy-2-methylpiperidin-1-yl)methanone(6)

A solution of (3R,6R)-6-methylpiperidin-3-ol (5.31 g, 46.1 mmol),2-(2H-1,2,3-triazol-2-yl)benzoic acid (10.5 g, 55.3 mmol), EDC (17.7 g,92.0 mmol), 1-hydroxy-7-azabenzotriazole (12.6 g, 92.0 mmol), andtriethylamine (19.3 mL, 138 mmol) in DMF (300 mL) was stirred at 50° C.overnight, then diluted with saturated aqueous sodium bicarbonate andextracted 3× with ethyl acetate. The organics were washed with brine,dried over magnesium sulfate, filtered, and concentrated. The crudematerial was purified by silica gel gradient chromatography (0-100%ethyl acetate in hexanes), providing the titled compound as a paleyellow solid. LRMS m/z (M+H) 287.3 found, 287.1 required.

Step 7: 2-Chloro-4-ethoxypyridine (7)

A solution of 2-chloropyridin-4-ol (1.50 g, 11.6 mmol) in DMF (20 mL)was treated with sodium hydride (0.602 g, 15.0 mmol). After 20 min.,iodoethane (1.12 mL, 13.9 mmol) was added. After 30 min., the mixturewas quenched with saturated aqueous ammonium chloride and water, andextracted 3× with ethyl acetate. The combined organic fractions werewashed with brine, dried over sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel gradientchromatography (0-20% ethyl acetate in hexanes), providing the titlecompound as a white solid. LRMS m/z (M+H) 158.1 found, 158.2 required.

Step 8:4-Ethoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine

A solution of[(2R,5R)-5-hydroxy-2-methylpiperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone(0.025 g, 0.087 mmol) in DMF (1 mL) was treated with sodium hydride (3.1mg, 0.131 mmol). After stirring ˜20 minutes, 2-chloro-4-ethoxypyridine(16.5 g, 0.105 mmol) was added and the reaction was heated to 50° C.overnight. Additional sodium hydride (1.6 mg, 0.065 mmol) was added, andthe reaction was heated to 80° C. for 4 h, then quenched with saturatedaqueous ammonium chloride and diluted with water. The mixture wasextracted 3× with ethyl acetate and the combined organic fractions werewashed with brine, dried over sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography(0-3% methanol in dichloromethane) to provide the title compound. HRMSm/z (M+H) 408.2016 found, 408.2030 required.

TABLE 1 The following compounds were prepared using the foregoingmethodology and general procedure described in Example 1, butsubstituting the appropriate 2-halopyridine for 2-chloro-4-ethoxypyridine, as described in the foregoing Reaction Schemesand Examples. The requisite starting materials were commerciallyavailable, described in the literature or readily synthesized by oneskilled in the art of organic synthesis from commercially availablereagents using conventional reactions without undue experimentation.

LRMS or HRMS Example R Name (M + H⁺) 2

4-methoxy-2-{[(3R,6R)-6-methyl- 1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3- yl]oxy}pyridine Calc'd 394.1876, found394.1871 3

3-bromo-4-methoxy-2-{[(3R,6R)-6- methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3- yl]oxy}pyridine Calc'd 472.0981, found472.0983 4

4-(benzyloxy)-2-{[(3R,6R)-6- methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3- yl]oxy}pyridine Calc'd 470.2188, found470.2201

EXAMPLE 5

4-(1-Methylethoxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridineStep 1:(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5S)-5-hydroxy-2-methylpiperidin-1-yl)methanone(8)

The title compound was prepared by the procedure described for thesynthesis of(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-hydroxy-2-methylpiperidin-1-yl)methanone(Example 1, 6), substituting benzyl(2R,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate (Example 1, 2) forbenzyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (Example 1,4). LRMS m/z (M+H) 287.4 found, 287.2 required.

Step 2:(3S,6R)-1-(2-(2H-1,2,3-Triazol-2-yl)benzoyl)-6-methylpiperidin-3-ylmethanesulfonate (9)

A solution of2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5S)-5-hydroxy-2-methylpiperidin-1-yl)methanone(0.300 g, 1.05 mmol), 4-dimethylaminopyridine (0.013 g, 0.10 mmol), andHunig's base (0.27 mL, 0.0016 mmol) in dichloromethane (10.5 mL) wascooled to 0° C. and treated with methanesulfonyl chloride (0.10 mL,0.0013 mmol). After 3 hours, the mixture was poured into saturatedaqueous sodium bicarbonate and extracted 2× with dichloromethane. Thecombined organic fractions were washed with brine, dried over sodiumsulfate, filtered, and concentrated in vacuo, providing the titlecompound as a sticky off-white foam which was used without furtherpurification. LRMS m/z (M+H) 365.3 found, 365.2 required.

Step 3:4-(1-Methylethoxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine

A solution of(3S,6R)-1-(2-(2H-1,2,3-triazol-2-yl)benzoyl)-6-methylpiperidin-3-ylmethanesulfonate (0.020 g, 0.055 mmol) and 4-isopropoxypyridin-2-ol(0.033 g, 0.22 mmol) in DMF (0.5 mL) was treated with cesium carbonate(0.036 g, 0.11 mmol) and heated to 100° C. overnight. The mixture wasfiltered and purified by reverse phase preparatory HPLC, providing thetitle compound. HRMS m/z (M+H) 422.2187 found, 422.2188 required.

EXAMPLE 6

4-Methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridineStep 1: (2R,5S)-Benzyl2-methyl-5-((methylsulfonyl)oxy)piperidine-1-carboxylate (10)

A solution (2R,5S)-benzyl 5-hydroxy-2-methylpiperidine-1-carboxylate(Example 1, 2, 10.0 g, 40.1 mmol), 4-dimethylaminopyridine (0.490 g,4.01 mmol), and Hunig's base (10.5 mL, 60.2 mmol) in dichloromethane(200 mL) was cooled to 0° C. and treated with a solution ofmethanesulfonyl chloride (3.91 mL, 50.1 mmol) in dichloromethane (67 mL)dropwise. After 2 hours, the mixture was diluted with water and 1 N HClto pH ˜5. The organic fraction was washed with brine, dried overmagnesium sulfate, filtered, and concentrated, providing the titlecompound as an orange oil which was used without further purification.LRMS m/z (M+H) 328.3 found, 328.2 required.

Step 2: (2R,5R)-Benzyl5-((4-methoxypyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate (11)

A solution of (2R,5S)-benzyl2-methyl-5-((methylsulfonyl)oxy)piperidine-1-carboxylate (0.800 g, 2.44mmol) in DMF (10 mL) was treated with 4-methoxypyridin-2-ol (0.459 g,3.67 mmol) and cesium carbonate (0.876 g, 2.69 mmol) and heated at 100°C. overnight. The reaction was diluted with saturated aqueous sodiumbicarbonate and extracted 2× with ethyl acetate. The combined organicfractions were washed with brine, dried over sodium sulfate, filtered,and concentrated in vacuo. The residue was purified by silica gelgradient chromatography (0-50% ethyl acetate in hexanes), providing thetitle compound LRMS m/z (M+H) 357.3 found, 357.3 required.

Step 3: 4-Methoxy-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine (12)

A solution of (2R,5R)-benzyl5-((4-methoxypyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate (0.730g, 2.048 mmol) and palladium (10 wt % on activated carbon, 0.011 g, 0.10mmol) in degassed methanol (10 mL) was stirred overnight under anatmosphere of hydrogen gas. The degassed mixture was then filtered overcelite, washing with methanol. The filtrate was concentrated in vacuo,providing the title compound which was used without furtherpurification. LRMS m/z (M+H) 223.3 found, 223.3 required.

Step 4: 2-(2H-Tetrazol-2-yl)benzoic acid (13)

To a 20 mL microwave tube was charged 2-iodobenzoic acid (1.85 g, 7.46mmol), cesium carbonate (4.06 g, 12.5 mmol), copper(I) iodide (0.128 g,0.671 mmol), and DMA (8.0 mL). N,N′-Dimethylglyine (0.131 g, 1.27 mmol)and tetrazole (1.29 g, 18.4 mmol) were added, and the solution wasirradiated in a microwave reactor at 100° C. for 1 hour. The reactionwas diluted with water and 1 N aqueous sodium hydroxide and washed withethyl acetate. The aqueous fraction was acidified with conc. HCl andextracted 2× with ethyl acetate. The combined organic fractions werewashed with brine, dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by silica gel gradientchromatography [0-85% (1% acetic acid in ethyl acetate) in hexanes],providing the title compound. ¹H NMR (400 MHz, CD₃OD): δ 7.72-7.84 (m, 3H), 8.07 (dd, J=7.6, 1.6 Hz, 1 H), 8.90 (s, 1 H) ppm. LRMS m/z (M+H)191.1 found, 191.2.

Step 5:4-Methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine

A solution of 4-methoxy-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine(0.016 g, 0.063 mmol), 2-(2H-tetrazol-2-yl)benzoic acid (0.010 g, 0.053mmol), EDC (0.015 g, 0.079 mmol), N-hydroxybenzotriazole (0.80 mg,0.0053 mmol), and triethylamine (0.018 mL, 0.13 mmol) in DMF (0.5 mL)was heated at 50° C. for 4.5 h. The mixture was filtered and purified byreverse phase preparatory HPLC, providing the titled compound. HRMS m/z(M+H) 395.1812 found, 395.1829 required.

Alternative Procedure A to Intermediate 12

tert-Butyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (14)

A solution of benzyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate(Example 1, 4, 34.76 g, 139 mmol), di-tert-butyl dicarbonate (33.5 g,153 mmol), and palladium (10 wt % on activated carbon, 1.0 g) indegassed EtOAc (500 mL) was stirred overnight under an atmosphere ofhydrogen gas. Additional palladium (0.2 g) was added and stirringcontinued for 3.5 h. The degassed mixture was filtered over celite,washing with EtOAc. The filtrate was concentrated and purified by silicagel gradient chromatography (0-75% EtOAc in hexanes), providing thetitled compound as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.40(t, J=6.8 Hz, 1H), 3.86-4.05 (m, 2H), 3.02 (dd, J=14.2, 1.8 Hz, 1H),2.22 (s, 1H), 2.01-2.13 (m, 1H), 1.59-1.82 (m, 2H) ppm. LRMS m/z (M+H)216.3 found, 216.2 required.

Alternative Procedure B to Intermediate 12

tert-Butyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate (14) Step1: (R)-1-(Benzyl(hydroxy)amino)hex-5-en-2-ol (16)

To a solution of (R)-1,2-epoxy-5-hexene (36.9 g, 376 mmol) andN-benzylhydroxylamine hydrochloride (50 g, 313 mmol) in degassedmethanol (500 mL) was added triethylamine (31.7 g, 313 mmol) (seeO'Neil, et al., Tet. Lett., 39, 9089-9092 (1998), O'Neil, et al.,Synlett, 5, 695-697 (2000)). The resulting mixture was stirred, under anitrogen atmosphere, at ambient temperature for 4 days. The reaction wasquenched with 5 wt % aqueous NaHCO₃ and then extracted 2× with EtOAc.The combined organic layers were concentrated, removing the aqueousphase that separated out part-way through the concentration, to affordthe title compound as a crude yellow oil which was used directly in thenext step, without further purification.

Step 2: (1S,2R,5R)-1-Benzyl-5-hydroxy-2-methylpiperidine 1-oxide (17)

A solution of (R)-1-(benzyl(hydroxy)amino)hex-5-en-2-ol (63.1 g, 285mmol) in degassed ethanol (316 mL) and water (316 mL) was stirred, undera nitrogen atmosphere, at approx. 80° C. for 3 nights. The reactionmixture was then partially concentrated to remove the ethanol, and theresulting aqueous solution was washed 5× with CH₂Cl₂. The resultingcrude aqueous solution of the title compound was used directly in thenext step, without further purification.

Step 3: tert-Butyl (2R,5R)-5-hydroxy-2-methylpiperidine-1-carboxylate(14)

To an aqueous solution (252 mL) of(1S,2R,5R)-1-benzyl-5-hydroxy-2-methylpiperidine 1-oxide (27.8 g, 125mmol) was added triethylamine (15.2 g, 151 mmol), ethanol (250 mL), andpalladium (20 wt % on activated carbon, 2.8 g). The mixture was stirredovernight under an atmosphere of hydrogen gas (5 barg) at 50° C. Thecatalyst was then removed by filtration, washing with ethanol. To theresulting aqueous ethanol solution (525 mL) of(3R,6R)-6-methylpiperidin-3-ol was added triethylamine (12.7 g, 125mmol) followed by a solution of di-tert-butyl dicarbonate (30.1 g, 138mmol) in ethanol (29 mL). The reaction was stirred overnight at ambienttemperature, and then concentrated to a volume of approx. 250 mL. Themixture was seeded with a small amount of title compound, aged atambient temperature, concentrated to approx. 150 mL, and then cooled to0° C. The resulting slurry was filtered, washing the solid with water.The resulting solid was dried to afford the title compound as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 4.35-4.46 (m, 1H), 3.98 (d, J=14.5 Hz,1H), 3.92 (br s, 1H), 3.03 (d, J=14.5 Hz, 1H), 2.01-2.13 (m, 2H),1.61-1.82 (m, 2H), 1.46 (s, 9H), 1.29 (br d, J=12.5 Hz, 1H), 1.13 (d,J=7.0 Hz, 3H) ppm.

Completion of Alternative Route to Intermediate 12:

Step 1: (2R,5R)-tert-butyl5-((4-methoxypyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate (18)

A solution of (2R,5R)-tert-butyl5-hydroxy-2-methylpiperidine-1-carboxylate (2.50 g, 11.6 mmol) in DMSO(23 ml) and DMF (3.8 ml) was treated with NaH (dry powder, 0.56 g, 23mmol). After stirring for ˜15 mins, 2-fluoro-4-methoxypyridine (2.21 g,17.4 mmol) was added and the reaction was heated at 50° C. overnight.The cooled reaction was quenched with saturated, aqu. NaHCO₃, dilutedwith water, and extracted 2× with EtOAc. The combined organics werewashed with brine, dried over MgSO₄, filtered, concentrated, dried, andpurified by silica gel gradient chromatography (0-40% EtOAc in hexanes),providing the titled compound as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.91 (d, J=5.8 Hz, 1H), 6.44 (dd, J=2.4, 5.8 Hz, 1H), 6.17 (d,J=2.4 Hz, 1H), 5.11 (br s, 1H), 4.53 (br s, 1H), 4.35 (d, J=14.8 Hz,1H), 3.79 (s, 3H), 3.05 (dd, J=1.6, 14.8 Hz, 1 H), 2.12-2.17 (m, 1H),1.88-1.92 (m, 2H), 1.30 (s, 9H), 1.18-1.35 (m, 1H), 1.18 (d, J=6.8 Hz,3H) ppm. LRMS m/z (M+H) 323.5 found, 323.4 required.

Step 2: 4-methoxy-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine (12)

A solution of (2R,5R)-tert-butyl5-((4-methoxypyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate (3.73 g,11.6 mmol in CH₂Cl₂ (5.4 ml) was cooled at −78° C. and treated with HCl,4 M in dioxane (20.3 mL). The reaction was allowed to warm to RT andstirred overnight, then concentrated in vacuo. The residue was taken upin EtOAc and free-based by addition of 1 N NaOH. The layers wereseparated and the aqueous portion was extracted 2× more with EtOAc. Thecombined organics were washed with brine, dried over MgSO4, filtered,concentrated. The crude material was purified by silica gel gradientchromatography (0-25% MeOH in CH₂Cl₂), providing the titled compound asa colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=6.0 Hz, 1H), 6.44(dd, J=2.4, 6.0 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 4.90-4.98 (m, 1H), 3.79(s, 3H), 3.38-3.49 (m, 1H), 2.59-2.70 (m, 2H), 2.19-2.25 (m, 1H),1.77-1.83 (m, 1H), 1.49-1.59 (m, 1H), 1.22-1.33 (m, 1H), 1.10 (d, J=6.4Hz, 3H) ppm. LRMS m/z (M+H) 223.1 found, 223.3 required.

TABLE 2 The following compounds were prepared using the foregoingmethodology and general procedure described in Example 6, butsubstituting the appropriate carboxylic acid for 2-(2H-tetrazol-2-yl)benzoic acid, and substituting the appropriate 2-hydroxypyridine for 4-methoxypyridin-2-ol (via first scheme with intermediate 10) or 2-fluoropyridine for 2-fluoro-4-methoxypyridine (via alternate scheme withintermediate 14), as described in the foregoing Reaction Schemes andExamples. The requisite starting materials were commerically available,described in the literature or readily synthesized by one skilled in theart of organic synthesis from commerically available reagents usingconventional reactions without undue experimentation.

Ex- LRMS or am- HRMS ple R R′ Name (M + H⁺)  7

iPr 4-(1- methylethoxy)- 2-{[(3R,6R)-6- methyl-1-{[2- (2H-tetrazol-2-yl)phenyl] carbonyl} piperidin-3- yl]oxy}pyridine Calc'd 423.2141, found423.2125  8

Et 4-ethoxy-2- {[(3R,6R)-6- methyl-1-{[2- (2H-tetrazol-2- yl)phenyl]carbonyl} piperidin-3- yl]oxy}pyridine Calc'd 409.1985, found 409.1970 9

Me 4-methoxy-2- {[(3R,6R)-6- methyl-1-{[4- (2H-1,2,3-triazol-2-yl)pyridin-3- yl]carbonyl} piperidin-3- yl]oxy}pyridine Calc'd395.1829, found 395.1838 10

Me 2-{[(3R,6R)-1- {[3-fluoro-2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}- 6-methylpiperidin- 3-yl]oxy}-4- methoxypyridine Calc'd412.1782, found 412.1786 11

Me 3-({(2R,5R)-5-[(4- methoxypyridin-2- yl)oxy]-2- methylpiperidin-1-yl}carbonyl)-4- (2H-1,2,3-triazol-2- yl)benzamide Calc'd 437.1934, found437.1935 12

Me 2-({(3R,6R)-1-[(2- cyclopropylphenyl) carbonyl]-6- methylpiperidin-3-yl}oxy)-4- methoxypyridine Calc'd 367.2018, found 367.2024 13

Me 4-methoxy-2- {[(3R,6R)-6- methyl-1-{[2- (trifluoromethyl)phenyl]carbonyl} piperidin-3-yl] oxy}pyridine Calc'd 395.158, found395.1581 14

Me 2-({(3R,6R)-1-[(2- ethoxyphenyl) carbonyl]-6- methylpiperidin-3-yl}oxy)-4- methoxypyridine Calc'd 371.1967, found 371.1973 15

Me 6-methoxy-3- ({(2R,5R)-5-[(4- methoxypyridin- 2-yl)oxy]-2-methylpiperidin- 1-yl}carbonyl)-2- phenylpyridine Calc'd 434.2076, found434.2082 16

Me 4-methoxy-2- ({(3R,6R)- 6-methyl-1-[(4- phenylisothiazol-5-yl)carbonyl] piperidin-3- yl}oxy)pyridine Calc'd 410.1535, found410.1537 17

Me 2-{[(3R,6R)-1- {[2-fluoro-6-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}- 6-methylpiperidin- 3-yl]oxy}-4- methoxypyridine Calc'd412.1779, found 412.1786 18

Me 6-methoxy-3- ({(2R,5R)-5-[(4- methoxypyridin- 2-yl)oxy]-2-methylpyridin-1- yl}carbonyl)-2- (2H-1,2,3-triazol- 2-yl)pyridine Calc'd425.1934, found 425.1938 19

Me 2-{[(3R,6R)-1- {[4-fluoro-2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}- 6-methylpiperidin- 3-yl]oxy}-4- methoxypyridine Calc'd412.1782, found 412.1781 20

Me 4-methoxy-2- {[(3R,6R)-1-{[4- methoxy-2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}- 6-methylpiperidin- 3-yl]oxy}pyridine Calc'd 424.1982,found 424.1979 21

Me 2-cyclopropyl- 6-methoxy-3- ({(2R,5R)-5-[(4- methoxypyridin-2-yl)oxy]-2- methylpiperidin-1- yl}carbonyl) pyridine Calc'd 398.2076,found 398.2083 22

Me 2-chloro-6- methoxy-3- ({(2R,5R)-5-[(4- methoxypyridin- 2-yl)oxy]-2-methylpiperidin-1- yl}carbonyl) pyridine Calc'd 392.1374, found 392.138023

iPr 2-{[(3R,6R)-1- {[4-fluoro-2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}- 6-methylpiperidin- 3-yl]oxy}-4-(1- methylethoxy)pyridine Calc'd 440.2095, found 440.2078 24

iPr 2-{[(3R,6R)-1- {[4-methoxy-2- (2H-1,2,3-triazol- 2-yl)phenyl]carbonyl}-6- methylpiperidin- 3-yl]oxy}-4-(1- methylethoxy) pyridineCalc'd 452.2294, found 452.2276 25

iPr 6-methoxy-3- {[(2R,5R)-2- methyl-5-{[4-(1- methylethoxy) pyridin-2-yl]oxy}piperidin-1- yl]carbonyl}-2- (2H-1,2,3-triazol- 2-yl)pyridineCalc'd 453.2246, found 453.2230 26

iPr 2-{[(3R,6R)-1- {[5-fluoro-2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}- 6-methylpiperidin- 3-yl]oxy}-4-(1- methylethoxy)pyridine Calc'd 440.2095, found 440.2078

EXAMPLE 27

(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanoneStep 1: 4-(2,2-difluoroethoxy)-2-fluoropyridine (20, Method A)

A solution of 2,2-difluoroethanol (5.25 g, 64.0 mmol) and2,4-difluoropyridine (10.5 g, 91.0 mmol) in DMF (107 ml), cooled at 0°C., was treated with NaH (dry powder, 1.69 g, 70.4 mmol) in 4 portions.After addition was complete, the reaction was maintained at 0° C.overnight. The reaction was carefully quenched by slow addition ofsaturated, aqu. NaHCO₃, then water. The solution was extracted 3× withEtOAc and the combined organics were washed with brine, dried overMgSO₄, filtered, and concentrated. The crude material was purified bysilica gel gradient chromatography (0-20% EtOAc in hexanes), providingthe titled compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.08(d, J=6.0 Hz, 1H), 6.75-6.77 (m, 1H), 6.42 (d, J=2.0 Hz, 1H), 6.11 (tt,J=54.8, 4.0 Hz, 1H), 4.25 (dt, J=12.8, 4.0 Hz, 2H) ppm. LRMS m/z (M+H)178.0 found, 178.1 required.

Step 1: 4-(2,2-difluoroethoxy)-2-fluoropyridine (20, Method B)

A solution of 2-fluoropyridin-4-ol (750 mg, 6.63 mmol) in DMF (20 mL)was treated with 1,1-difluoro-2-iodoethane (1655 mg, 8.62 mmol) andK₂CO₃ (1375 mg, 9.95 mmol) and heated at 60° C. overnight. The reactionwas diluted with EtOAc and washed with saturated, aqu. NaHCO₃, then withbrine. The organics were dried over MgSO₄, filtered, and concentrated.The crude material was purified by silica gel gradient chromatography(0-30% EtOAc in hexanes), providing the titled compound as a colorlessoil.

Step 2: (2R,5R)-tert-butyl5-((4-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate(21)

A solution of (2R,5R)-tert-butyl5-hydroxy-2-methylpiperidine-1-carboxylate (7.30 g, 33.9 mmol) in THF(75 ml) was cooled to 15° C. KOtBu (1 M in THF, 37.3 ml) was addedslowly via addition funnel while maintaining the reaction temperaturebelow 20° C. When addition was complete, the reaction was stirred for 25mins while warming to RT, then re-cooled in a water bath while adding4-(2,2-difluoroethoxy)-2-fluoropyridine (6.00 g, 33.9 mmol) in THF (38ml) quickly dropwise. The reaction temperature was maintained below 25°C. during addition. When addition was complete, the reaction was warmedto RT. After ˜40 mins, the reaction was cooled at 0° C. and quenched byaddition of saturated, aqu. NH₄Cl. The solution was extracted 2× withEtOAc and the combined organics were washed with brine, dried overMgSO₄, filtered, and concentrated. The crude material was purified bysilica gel gradient chromatography (0-50% EtOAc in hexanes), providingthe titled compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d,J=6.0 Hz, 1H), 6.48 (dd, J=5.6, 2.0 Hz, 1H), 6.17 (d, J=3.2 Hz, 1H),6.08 (tt, J=54.8, 4.0 Hz, 1H), 5.12 (br s, 1H), 4.51 (br s, 1H), 4.34(d, J=14.8 Hz, 1H), 4.09-4.20 (m, 2H), 3.05 (dd, J=14.4, 1.6 Hz, 1H),2.10-2.18 (m, 1H), 1.88-1.92 (m, 2H), 1.24-1.36 (m, 10H), 1.18 (d, J=6.8Hz, 3H) ppm. LRMS m/z (M+H) 373.2 found, 373.4 required.

Step 3:4-(2,2-difluoroethoxy)-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine(22)

A solution of (2R,5R)-tert-butyl5-((4-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate(9.61 g, 25.8 mmol) in CH₂Cl₂ (12 ml) was cooled at −78° C. and treatedwith HCl (4 M in dioxane, 45 mL). The reaction was warmed to RT. After˜30 mins, the reaction was concentrated in vacuo. The residue wasbasified by addition of 1 N NaOH and extracted 2× with EtOAc. Thecombined organics were washed with brine, dried over MgSO₄, filtered,and concentrated. The crude material was purified by silica gel gradientchromatography (0-25% MeOH in CH₂Cl₂), providing the titled compound asa colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J=6.0 Hz, 1H), 6.46(dd, J=6.0, 2.4 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 6.08 (tt, J=54.8, 4.0Hz, 1H), 4.91-4.99 (m, 1H), 4.17 (dt, J=13.2, 4.0 Hz, 2H), 3.48 (s, 1H),3.38-3.43 (m, 1H), 2.59-2.71 (m, 2H), 2.18-2.25 (m, 1H), 1.77-1.83 (m,1H), 1.48-1.58 (m, 1H), 1.22-1.33 (m, 1H), 1.08 (d, J=6.4 Hz, 3H) ppm.LRMS m/z (M+H) 273.1 found, 273.3 required.

Step 4:(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone

A solution of4-(2,2-difluoroethoxy)-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine(33 mg, 0.11 mmol), 2-(2H-1,2,3-triazol-2-yl)benzoic acid (20 mg, 0.11mmol), HOBT (1.6 mg, 0.011 mmol), and EDC (30 mg, 0.16 mmol) in DMF (1.1ml) was treated with triethylamine (37 μL, 0.26 mmol) and heated at 50°C. overnight. Additional 2-(2H-1,2,3-triazol-2-yl)benzoic acid (1.3equiv.), EDC (1 equiv.), and triethylamine (1 equiv.) were added andheating continued overnight. The reaction was diluted with saturated,aqu. NaHCO₃ and extra water, then extracted 2× with EtOAc. The combinedorganics were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The crude material was purified by silica gel gradientchromatography (0-40% EtOAc in hexanes), then further purified byreverse phase HPLC, providing the titled compound as a tacky solid. HRMSm/z (M+H) 444.1827 found, 444.1842 required.

TABLE 3 The following compounds were prepared using the foregoingmethodology and general procedure described in Example 27, butsubstituting the appropriate carboxylic acid for2-(2H-1,2,3-triazol-2-yl) benzoic acid, and substituting the appropriatealcohol for 2,2- difluoroethanol (Method A) or the appropriate alkylhalide for 1,1,-fifluoro-2-iodoethane (Method B), as described in theforegoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesis fromcommercially available reagents using conventional reactions withoutundue experimentation.

LRMS or HRMS Example R R′ Name (M + H⁺) 28

CH₂CF₃ (2-(2H-1,2,3-triazol-2- yl)phenyl)((2R,5R)-2-methyl-5-((4-(2,2,2- trifluoroethoxy)pyridin-2- yl)oxy)piperidin-1-yl)methanone Calc'd 462.1748, found 462.1732 29

CH₂CHF₂ 4-(2,2-difluoroethoxy)-2- {[(3R,6R)-6-methyl-1-{[2-(2H-tetrazol-2- yl)phenyl]carbonyl}piperidin- 3-yl]oxy}pyridine Calc'd445.1797, found 445.1794 30

CH₂CF₃ 2-{[(3R,6R)-6-methyl-1-{[2- (2H-tetrazol-2-yl)phenyl]carbonyl}piperidin- 3-yl]oxy}-4-(2,2,2-trifluoroethoxy)pyridine Calc'd 463.1703, found 463.1683 31

CH₂CHF₂ 4-(2,2-difluoroethoxy)-2- {[(3R,6R)-6-methyl-1-({2-[(methylsulfonyl)methyl] phenyl}carbonyl)piperidin-3- yl]oxy}pyridineCalc'd 469.2, found 469.1 32

CH₂CHF₂ 1-(2-{[(2R,5R)-5-{[4-(2,2- difluoroethoxy)pyridin-2-yl]oxy}-2-methylpiperidin-1- yl]carbonyl}phenyl)cyclopropanecarbonitrile Calc'd 442.2, found 442.1 33

CH₂CHF₂ 2-{[(2R,5R)-5-{[4-(2,2- difluoroethoxy)pyridin-2-yl]oxy}-2-methylpiperidin-1- yl]carbonyl}-3-(2H-1,2,3-triazol-2-yl)pyridine Calc'd 445.2, found 445.2 34

CH₂CHF₂ 4-(2,2-difluoroethoxy)-2- {[(3R,6R)-1-{[3-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl]carbonyl}-6- methylpiperidin-3-yl]oxy}pyridine Calc'd 462.2, found 462.4 35

CH₂CHF₂ 4-(2,2-difluoroethoxy)-2- {[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl]carbonyl}-6- methylpiperidin-3-yl]oxy}pyridine Calc'd 462.2, found 462.2 36

CH₂CHF₂ 4-(2,2-difluoroethoxy)-2- {[(3R,6R)-1-{[2-fluoro-6-(2H-1,2,3-triazol-2- yl)phenyl]carbonyl}-6- methylpiperidin-3-yl]oxy}pyridine Calc'd 462.2, found 462.3 37

CH₂CHF₂ 4-(2,2-difluoroethoxy)-2- {[(3R,6R)-6-methyl-1-{[2-(3-methyl-1,2,4-oxadiazol-5- yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine Calc'd 459.2, found 459.4 38

CH₂CHF₂ 4-(2,2-difluoroethoxy)-2- {[(3R,6R)-6-methyl-1-{[2-(5-methyl-1,2,4-oxadiazol-3- yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine Calc'd 459.2, found 459.4

EXAMPLE 39

2-{[(3R,6R)-6-Methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-ol

A solution of4-(benzyloxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine(Example 6, 0.220 g, 0.469 mmol) and palladium (10 wt % on activatedcarbon, 5.0 mg) in degassed methanol (5 mL) was stirred for 3.5 hoursunder an atmosphere of hydrogen gas. The degassed mixture was thenfiltered over celite, washing with EtOH. The filtrate was concentratedto give the crude title compound which was used without furtherpurification. HRMS m/z (M+H) 380.1723 found, 380.1717 required.

EXAMPLE 40

4-(Cyclopropyloxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}pyridine

A solution of2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-ol(Example 39, 0.012 g, 0.032 mmol), cyclopropyl bromide (5.7 mg, 0.047mmol), and potassium carbonate (5.7 mg, 0.041 mmol) in DMF (1 mL) washeated to 40° C. overnight. Additional cyclopropyl bromide (5.7 mg,0.047 mmol) was added, and the mixture was heated at 40° C. for 72 h,then filtered and purified by reverse phase HPLC, providing the titlecompound. HRMS m/z (M+H) 420.2033 found, 420.3032 required.

TABLE 4 The following compounds were prepared using the foregoingmethodology and general procedure described in Example 40, butsubstituting the appropriate alkyl halide for cyclopropyl bromide, asdescribed in the foregoing Reaction Schemes and Examples. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis from commercially available reagents using conventionalreactions without undue experimentation.

LRMS or HRMS Example R Name (M + H⁺) 41

2-{[(3R,6R)-6-methyl-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3- yl]oxy}-4-(oxetan-3-yloxy)pyridineCalc'd 436.1981, found 436.1986 42

4-(2-methylpropoxy)-2-{[(3R,6R)-6- methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3- yl]oxy}pyridine Calc'd 436.2345, found436.2350 43

2-{[(3R,6R)-6-methyl-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3- yl]oxy}-4-propoxypyridine Calc'd422.2188, found 422.2189

EXAMPLE 44

2-(2-{[(2R,5R)-2-Methyl-5-{[4-(1-methylethoxy)pyridin-2-yl]oxy}piperidin-1-yl]carbonyl}phenyl)pyrimidineStep 1: 4-Isopropoxy-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine(23)

The title compound was prepared by the procedure described for thesynthesis of 4-methoxy-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine(Example 6, 12), substituting 4-isopropoxypyridin-2-ol for4-methoxypyridin-2-ol. HRMS m/z (M+H) 433.2234 found, 433.2236 required.

Step 2:2-(2-{[(2R,5R)-2-Methyl-5-{[4-(1-methylethoxy)pyridin-2-yl]oxy}piperidin-1-yl]carbonyl}phenyl)pyrimidine

A solution of4-isopropoxy-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine hydrogenchloride (0.010 g, 0.036 mmol), 2-(pyrimidin-2-yl)benzoic acid (8.0 mg,0.040 mmol), and triethylamine (0.013 mL, 0.091 mmol) in DMF (0.3 mL)was treated with2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P,50% in EtOAc, 0.043 mL, 0.073 mmol) and stirred at RT overnight.Additional2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P,50% in EtOAc, 0.043 mL, 0.073 mmol) was added, and the reaction washeated at 50° C. for 2.5 hours, filtered, and purified by reverse phasepreparatory HPLC, providing the title compound. HRMS m/z (M+H) 433.2234found, 433.2236 required.

TABLE 5 The following compounds were prepared using the foregoingmethodology and general procedure described in Example 44, butsubstituting the appropriate piperidine and pyrimidine carboxylic acid(or potassium carboxylate), as described in the foregoing ReactionSchemes and Examples. The requisite starting materials were commerciallyavailable, described in the literature or readily synthesized by oneskilled in the art of organic synthesis from commercially availablereagents using conventional reactions without undue experimentation.

LRMS or HRMS Example R R′ Name (M + H⁺) 45

CH₂CHF₂ 2-(2-{[(2R,5R)-5-{[4-(2,2- difluoroethoxy)pyridin-2- yl]oxy}-2-methylpiperidin-1- yl]carbonyl}phenyl) pyrimidine Calc'd 455.1889, found455.1872 46

CH₂CHF₂ 2-(2-{[(2R,5R)-5-{[4-(2,2- difluoroethoxy)pyridin-2- yl]oxy}-2-methylpiperidin-1- yl]carbonyl}-5- fluorophenyl)pyrimidine Calc'd 473.2,found 473.4 47

CH₂CHF₂ 2-(2-{[(2R,5R)-5-{[4-(2,2- difluoroethoxy)pyridin-2- yl]oxy}-2-methylpiperidin-1- yl]carbonyl}pyridin-3- yl)pyrimidine Calc'd 456.2,found 456.3

EXAMPLE 48

4-Methoxy-3-methyl-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine

A solution of3-bromo-4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine(Example 4, 0.020 g, 0.042 mmol) in THF (1 mL) under an atmosphere ofnitrogen was treated with dimethylzinc (1.0 M in THF, 0.085 mL, 0.085mmol) and tetrakis(triphenylphosphine)palladium(0) (4.9 mg, 0.0042 mmol)and heated to 80° C. for 4 h. Additional dimethylzinc (1.0 M in THF,0.085 mL, 0.085 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.9mg, 0.0042 mmol) were added, and the mixture was heated to 100° C.overnight. The reaction was quenched with saturated aqueous ammoniumchloride, stirred with Quadrapure™ for 30 min, filtered, and purified byreverse phase preparatory HPLC, providing the title compound. HRMS m/z(M+H) 408.2036 found, 408.2030 required.

EXAMPLE 49

2,4-Dimethoxy-6-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridineStep 1: 2-Chloro-3-fluoro-4-methoxypyridine (24)

A solution of 2,4-dichloro-3-fluoropyridine (0.200 g, 1.20 mmol) in DMF(2.4 mL) was treated with sodium methoxide (0.072 g, 1.3 mmol) andheated at 50° C. overnight. The mixture was quenched with saturatedaqueous ammonium chloride, diluted with water, and extracted 3× withethyl acetate. The combined organic fractions were washed with brine,dried over sodium sulfate, filtered, and concentrated. The residue waspurified by silica gel gradient chromatography (0-20% ethyl acetate inhexanes), providing the title compound as a white solid. LRMS m/z (M+H)162.1 found, 162.0 required.

Step 2:3-Fluoro-4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine

The title compound was prepared by the procedure described for thesynthesis of4-ethoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine(Example 1), substituting 2-chloro-3-fluoro-4-methoxypyridine for2-chloro-4-ethoxypyridine. HRMS m/z (M+H) 412.1761 found, 412.1782required.

EXAMPLE 50

Step 1:3-Ethenyl-4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine

To a solution of3-bromo-4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine(Example 4, 0.168 g, 0.356 mmol), potassium vinyltrifluoroborate (0.072g, 0.53 mmol), and cesium carbonate (0.232 g, 0.711 mmol) in THF (1.8mL) and water (0.2 mL) under an atmosphere of nitrogen was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.026 g, 0.036 mmol). The reaction was sealed andstirred at 100° C. overnight, then diluted with ethyl acetate and washedwith saturated aqueous sodium bicarbonate and brine, dried over sodiumsulfate, filtered, and concentrated. The residue was purified by silicagel gradient chromatography (0-50% ethyl acetate in hexanes), providingthe title compound as an orange oil. HRMS m/z (M+H) 420.2035 found,420.2030 required.

Step 2:4-Methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine-3-carbaldehyde

To a solution of3-ethenyl-4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine(0.090 g, 0.22 mmol) in a 2:1 mixture of THF:water (3 mL) was addedsodium periodate (0.115 g, 0.536 mmol) followed by osmium tetroxide(2.5% by wt in water, 0.03 mL, 0.002 mmol). After 4 h, the reaction waspartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic layer was washed with water and brine, driedover sodium sulfate, filtered, and concentrated. The residue waspurified by reverse phase preparatory HPLC, providing the titlecompound. HRMS m/z (M+H) 422.1831 found, 422.1825 required.

TABLE 6 The following compound was prepared using the foregoingmethodology and general procedure described in Example 50, butsubstituting the appropriate alkene for3-ethenyl-4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine,as described in the foregoing Reaction Schemes and Examples. Therequisite starting materials were commercially available, described inthe literature or readily synthesized by one skilled in the art oforganic synthesis from commercially available reagents usingconventional reactions without undue experimentation.

LRMS or HRMS Example R Name (M + H⁺) 51

1-(4-methoxy-2- {[(3R,6R)-6- methyl-1-{[2-(2H- 1,2,3-triazol-2-yl)phenyl]carbonyl} piperidin-3- yl]oxy}pyridin- 3-yl)ethanone Calc'd436.1981, found 436.1979

EXAMPLE 52

(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-((4-(difluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanoneStep 1: 2-Fluoro-4-((4-methoxybenzyl)oxy)pyridine

To a solution of para-methoxybenzyl alcohol (1.92 g, 13.9 mmol) in DMF(15 mL) was added sodium hydride (60% dispersion in mineral oil, 1.10 g,27.5 mmol) at 0-5° C. in portions. After stirring for 15 min at RT, asolution of 2,4-difluoropyridine (2.00 g, 17.4 mmol) in DMF (5 mL) wasadded. The resulting mixture was stirred RT for 3 h. The mixture wasquenched with saturated NH₄Cl and extracted 3× with EtOAc. The combinedorganic layers were washed with brine, dried over sodium sulfate,filtered and concentrated. The residue was purified by silica gelgradient chromatography (1:10 to 1:2 EtOAc in petroleum ether),providing the title compound as a white solid. LRMS m/z (M+H) 234.1found, 234.1 required.

Step 2:(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-((4-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone

To a solution of(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-hydroxy-2-methylpiperidin-1-yl)methanone(100 mg, 0.35 mmol) in DMF (3 mL) was added sodium hydride (60%dispersion in mineral oil, 42 mg, 1.05 mmol) at 0˜5° C. The mixture wasstirred at RT for 30 min, then 2-fluoro-4-((4-methoxybenzyl)oxy)pyridine(163 mg, 0.7 mmol) was added and the resulting mixture was stirred at RTovernight. The mixture was quenched with saturated and extracted 3× withEtOAc. The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated. The residue was purified bysilica gel gradient chromatography (1:10 to 1:3 EtOAc in petroleumether), providing the title compound as yellow oil. LRMS m/z (M+H) 500.2found, 500.2 required.

Step 3:(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-((4-hydroxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone

A mixture of2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(4-methoxybenzyl)oxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone(145 mg, 0.29 mmol) and palladium on carbon (10 wt %, 50 mg) in MeOH (10mL) was stirred at RT under 1 atm of H₂ for 3 h. The mixture wasfiltered over celite and the filtrate was concentrated and dried to givethe title compound as white solid, which was used in the next stepwithout further purification. LRMS m/z (M+H) 380.2 found, 380.2 required

Step 4:(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-((4-(difluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone

To a solution of(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-hydroxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)-methanone(50 mg, 0.132 mmol) in DMF (10 mL) was added potassium carbonate (456mg, 3.3 mmol). After the mixture was stirred for 30 min, sodium2-chloro-2,2-difluoroacetate (60.3 mg, 0.396 mmol) was added. Theresulting mixture was stirred at 80° C. for 1.5 h. The reaction wascooled to RT and the mixture was quenched with water and extracted 3×with EtOAc. The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated. The residue was purifiedby prep-HPLC to give the title compound as white solid. LRMS m/z (M+H)430.2 found, 430.2 required.

EXAMPLE 53

(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-((4-(fluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanoneStep 1: Methylene bis(4-methylbenzenesulfonate)

A mixture of tosylsilver (3 g, 10.7 mmol) and diiodomethane (1.43 g,4.43 mmol) in acetonitrile (30 mL) was refluxed under nitrogenatmosphere overnight. The mixture was cooled to RT and then filtered.The filtrate was concentrated and the solid was dissolveddichloromethane (50 mL). The resulting mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound as whitesolid, which was used in the next step directly.

Step 2: Fluoromethyl 4-methylbenzenesulfonate

A mixture of methylene bis(4-methylbenzenesulfonate) (1.6 g, 4.48 mmol)and TBAF (1.15 g, 4.48 mmol) in acetonitrile (15 mL) was heated at 80°C. overnight. The mixture was cooled to RT and concentrated in vacuo.The residue was purified by silica gel gradient chromatography (1:5EtOAc in petroleum ether), providing the title compound as a colorlessoil.

Step 3:(2-(2H-1,2,3-Triazol-2-yl)phenyl)((2R,5R)-5-((4-(fluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone

A mixture of fluoromethyl 4-methylbenzenesulfonate (55 mg, 0.27 mmol),(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-(4-hydroxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone(85 mg, 0.22 mmol), and potassium carbonate (62 mg, 0.45 mmol) inacetone (20 mL) was heated at reflux overnight. The mixture was cooledto RT and concentrated in vacuo. The residue was extracted withdichloromethane/water and the organic layer was washed with brine, driedover sodium sulfate, filtered, and concentrated. The residue waspurified by prep-HPLC to give the title compound as white solid. LRMSm/z (M+H) 412.2 found, 412.2 required.

EXAMPLE 54

(2-(2H-1,2,3-Triazol-2-yl)thiophen-3-yl)((2R,5R)-5-((4-(difluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanoneStep 1: (2R,5R)-tert-Butyl5-((4-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate

To a solution of (2R,5R)-tert-butyl5-hydroxy-2-methylpiperidine-1-carboxylate (500 mg, 2.32 mmol) in DMF(10 mL) was added sodium hydride (60% dispersion in mineral oil, 278 mg,6.95 mmol) at 0° C. The mixture was stirred at RT for 30 min and cooledto 0° C., then 2-fluoro-4-((4-methoxybenzyl)oxy)pyridine (1080 mg, 4.63mmol) was added. The resulting mixture was warmed to RT and stirred for4 h. The mixture was quenched with saturated NH₄Cl and extracted withEtOAc. The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrate. The residue was purified bysilica gel gradient chromatography (1:5 EtOAc in petroleum ether),providing the title compound as light yellow oil. LRMS m/z (M+H) 429.1found, 429.1 required.

Step 2: (2R,5R)-tert-Butyl5-((4-hydroxypyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate

A mixture of(2R,5R)-tert-butyl-5-((4-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate(550 mg, 1.28 mmol) and palladium on carbon (10 wt %, 100 mg) inmethanol (15 mL) was stirred at room temperature under a hydrogenatmosphere for 1.5 h. The mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound as a colorless oil,which was used in the next step directly. LRMS m/z (M+H) 309.2 found,309.2 required.

Step 3: (2R,5R)-tert-Butyl5-((4-(difluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate

A mixture of (2R,5R)-tert-butyl5-((4-hydroxypyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate (380 mg,1.23 mmol), sodium 2-chloro-2,2-difluoroacetate (375 mg, 2.47 mmol), andpotassium carbonate (1.7 g, 12.3 mmol) in DMF (20 mL) was stirred at 80°C. overnight. The reaction was cooled to RT, quenched with water, andextracted with EtOAc. The combined organic layers were washed withbrine, dried over sodium sulfate, filtered, and concentrated. Theresidue was purified by silica gel gradient chromatography (1:5 EtOAc inpetroleum ether), providing the title compound as a colorless oil. LRMSm/z (M+H) 359.1 found, 359.1 required.

Step 4:4-(Difluoromethoxy)-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine

To a solution of (2R,5R)-tert-butyl5-((4-(difluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate(205 mg, 0.573 mmol) in dichloromethane (10 mL) was addedtrifluoroacetic acid (5 mL) at 0° C. The mixture was allowed to heat toRT and stirred for 3 h. The mixture was concentrated in vacuo to givethe title compound as an oil, which was used in the next step directly.LRMS m/z (M+H) 259.2 found, 259.2 required.

Step 5:(2-(2H-1,2,3-Triazol-2-yl)thiophen-3-yl)((2R,5R)-5-((4-(difluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone

A mixture of4-(difluoromethoxy)-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine (50mg, 0.134 mmol), DIPEA (135 mg, 1.05 mmol), HATU (76.5 mmol, 0.2 mmol),and 2-(2H-1,2,3-triazol-2-yl)thiophene-3-carboxylic acid (30 mg, 0.154mmol) in DMF (2 mL) was stirred at room temperature overnight. Themixture was filtered and purified by prep-HPLC to give the titlecompound as a white solid. LRMS m/z (M+H) 436.1 found, 436.1 required.

TABLE 7 The following compound was prepared using the foregoingmethodology and general procedure described in Example 54, butsubstituting the appropriate acid for2-(2H-1,2,3-triazol-2-yl)thiophene-3-carboxylic acid, as described inthe foregoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesis fromcommercially available reagents using conventional reactions withoutundue experimentation.

Ex- LRMS am- (M + ple R Name H⁺) 55

4-(difluoromethoxy)- 2-{[(3R,6R)- 6-methyl-1- {[4-(2H-1,2,3-triazol-2-yl) thiophen-3- yl]carbonyl} piperidin- 3-yl]oxy}pyridineCalc'd 436.1, found 436.1 56

1-(2-{[(2R,5R)- 5-{[4- (difluoromethoxy) pyridin-2-yl]oxy}-2-methylpiperidin-1- yl]carbonyl}phenyl) cyclopropane- carbonitrile Calc'd428.1, found 428.1 57

4-(difluoromethoxy)- 2-{[(3R,6R)-6- methyl-1-{[2-(2H-tetrazol-2-yl)phenyl] carbonyl}piperidin- 3-yl]oxy}pyridine Calc'd431.2, found 431.1

EXAMPLE 58

((2R,5R)-5-((4-Methoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanoneStep 1: (2R,5R)-tert-Butyl5-((4-bromopyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate

To a solution of (2R,5R)-tert-butyl5-hydroxy-2-methylpiperidine-1-carboxylate (200 mg, 0.93 mmol) in DMF(2.0 mL) was added sodium hydride (60% dispersion in mineral oil, 74 mg,1.9 mmol) at 0° C. After the mixture was stirred at 0° C. for 0.5 h, asolution of 4-bromo-2-fluoropyridine (92 mg, 0.53 mmol) in DMF (0.5 ml)was added. The resulting mixture was allowed to warm to RT and stirredfor 4 h, then poured into water and extracted 3× with EtOAc. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, and concentrated. The combined organic layers were washed withbrine, dried over sodium sulfate, filtered, and concentrated. Theresidue was purified by silica gel gradient chromatography (1:5 EtOAc inpetroleum ether), providing the title compound as a pale yellow oil.LRMS m/z (M+H) 371.1, 373.1 found, 371.1, 373.1 required.

Step 2: (2R,5R)-tert-Butyl5-((4-methoxypyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate

To a solution of (2R,5R)-tert-butyl5-((4-bromopyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate (300 mg,0.81 mmol) in methanol (3 ml) was added sodium methanolate (87 mg, 1.62mmol). The mixture was stirred at 70° C. overnight. After cooling to RT,the mixture was concentrated in vacuo. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered, andconcentrated. The residue was purified by silica gel gradientchromatography (1:5 EtOAc in petroleum ether), providing the titlecompound as a pale yellow oil. LRMS m/z (M+H) 323.1 found, 323.1required.

Step 3: 4-Methoxy-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine

A solution of (2R,5R)-tert-butyl5-((4-methoxypyridin-2-yl)oxy)-2-methylpiperidine-1-carboxylate (100 mg,0.31 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (1 mL) wasstirred at RT for 0.5 h, then concentrated in vacuo to give the titlecompound as a yellow oil, which was used directly without any furtherpurification. LRMS m/z (M+H) 223.1 found, 223.1 required.

Step 4:((2R,5R)-5-((4-Methoxypyridin-2-yl)oxy)-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone

A solution of 4-methoxy-2-(((3R,6R)-6-methylpiperidin-3-yl)oxy)pyridine(100 mg, 0.45 mmol), HATU (342 mg, 0.90 mmol), DIPEA (173 mg, 1.35mmol), and 2-(pyrimidin-2-yl)thiophene-3-carboxylic acid (85 mg, 0.37mmol) in dichloromethane (3 mL) was stirred at RT for 9 h. The mixturewas poured into water and extracted 3× with EtOAc. The combined organiclayers were washed with brine, dried over magnesium sulfate, filtered,and concentrated. The residue was purified by prep-HPLC to give thetitle compound as a white solid. LRMS m/z (M+H) 411.1 found, 411.1required.

TABLE 8 The following compound was prepared using the foregoingmethodology and general procedure described in Example 58, butsubstituting the appropriate acid for2-(pyrimidin-2-yl)thiophene-3-carboxylic acid, as described in theforegoing Reaction Schemes and Examples. The requisite startingmaterials were commercially available, described in the literature orreadily synthesized by one skilled in the art of organic synthesis fromcommercially available reagents using conventional reactions withoutundue experimentation.

LRMS Example R Name (M + H⁺) 59

4-methoxy-2- {[(3R,6R)-6-methyl-1- {[2-(2H-1,2,3-triazol-2-yl)thiophen-3- yl]carbonyl}piperidin- 3-yl]oxy}pyridine Calc'd 400.1,found 400.1

EXAMPLE 60

(2-(2H-1,2,3-Triazol-2-yl)thiophen-3-yl)((2R,5R)-5-((4-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanoneStep 1: (3R,6R)-6-Methylpiperidin-3-ol (13)

To a solution of (2R,5R)-tert-butyl5-hydroxy-2-methylpiperidine-1-carboxylate (1.0 g, 4.65 mmol) in EtOAc(10 mL) was added HCl in EtOAc (4 M, 20 mL) at 0° C. The reaction waswarmed to RT and stirred for 4 h. The mixture was concentrated in vacuoto give the title compound which was used without further purification.LRMS m/z (M+H) 116.1 found, 116.1 required.

Step 2:(2-(2H-1,2,3-Triazol-2-yl)thiophen-3-yl)((2R,5R)-5-hydroxy-2-methylpiperidin-1-yl)methanone

To a solution of 2-(2H-1,2,3-triazol-2-yl)thiophene-3-carboxylic acid(1.0 g, 5.12 mmol) in SOCl₂ (10 mL) was stirred at 80° C. for 0.5 h.After cooling to RT, the mixture was concentrated in vacuo. The residuewas dissolved in dichloromethane (15 mL) and the resulting solution wasdropwise added to a solution of DIPEA (360 mg, 23.6 mmol) and(3R,6R)-6-methylpiperidin-3-ol (800 mg, 4.65 mmol) in dichloromethane(10 mL) at 0° C. The resulting mixture was stirred at RT for 9 h,quenched with water (20 mL), and extracted 3× with dichloromethane. Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by prep-TLC (1:1 EtOAc inpetroleum ether) to give the title compound as a yellow solid. LRMS m/z(M+H) 293.1 found, 293.1 required.

Step 3: 4-(2,2-Difluoroethoxy)-2-fluoropyridine

To a solution of 2,2-difluoroethanol (200 mg, 2.44 mmol) in DMF (4.0 mL)was added sodium hydride (60% dispersion in mineral oil, 195 mg, 4.88mmol) at 0° C. and the mixture was stirred at 0° C. for 0.5 h. Asolution of 2,4-difluoropyridine (337 mg, 2.93 mmol) in DMF (0.5 ml) wasadded. The resulting mixture was warmed to RT and stirred for 2 h, thenpoured into water and extracted 3× with EtOAc. The combined organiclayers were washed with brine, dried over magnesium sulfate, andconcentrated in vacuo. The residue was purified by silica gel gradientchromatography (1:5 EtOAc in petroleum ether) to give the title compoundas a colorless oil. LRMS m/z (M+H) 178.0 found, 178.0 required.

Step 4:(2-(2H-1,2,3-Triazol-2-yl)thiophen-3-yl)((2R,5R)-5-((4-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone

To a solution of(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)((2R,5R)-5-hydroxy-2-methylpiperidin-1-yl)methanone(145 mg, 0.50 mmol) in DMF (5 mL) was added sodium hydride (60%dispersion in mineral oil, 40 mg, 1.0 mmol) at 0° C. The suspension wasstirred for 0.5 h and 4-(2,2-difluoroethoxy)-2-fluoropyridine (105 mg,0.60 mmol) was added. The reaction mixture was warmed to RT and stirredfor 9 h, quenched with saturated, aqueous NH₄Cl, diluted with saturated,aqueous NaHCO₃, and extracted 2× with EtOAc. The organic layers werecombined, washed with water and brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified by silicagel gradient chromatography (1:2 EtOAc in petroleum ether) to give thetitle compound as a white solid. LRMS m/z (M+H) 450.1 found, 450.1required.

TABLE 9 The following compound was prepared using the foregoingmethodology and general procedure described in Example 60, butsubstituting the appropriate pyridine for 4-(2,2-difluoroethoxy)-2-fluoropyridine, as described in the foregoing Reaction Schemes andExamples. The requisite starting materials were commercially available,described in the literature or readily synthesized by one skilled in theart of organic synthesis from commerically available reagents usingconventional reactions without undue experimentation.

LRMS Example R Name (M + H⁺) 61

4-(1-methylethoxy)-2- {[(3R,6R)-6-methyl-1-{[2- (2H-1,2,3-triazol-2-yl)thiophen-3- yl]carbonyl}piperidin- 3-yl]oxy}pyridine Calc'd 428.2,found 428.2 62

4-ethoxy-2-{[(3R,6R)-6- methyl-1-{[2-(2H-1,2,3- triazol-2-yl)thiophen-3-yl]carbonyl}piperidin-3- yl]oxy}pyridine Calc'd 414.2, found 414.1 63

2-{[(3R,6R)-6-methyl-1- {[2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl]carbonyl} piperidin-3-yl]oxy}-4-(2,2,2-trifluoroethoxy) pyridine Calc'd 468.1, found 468.1

EXAMPLE 64

((2R,5R)-5-((4-(2,2-Difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanoneStep 1:((2R,5R)-5-Hydroxy-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone

To a suspension of 2-(pyrimidin-2-yl)thiophene-3-carboxylic acid (300mg, 1.46 mmol) in dichloromethane (15 mL) was added SOCl₂ (347 mg, 2.91mmol). The mixture was heated at 40° C. for 2 h. After cooling to RT,the mixture was concentrated in vacuo and was added dropwise to asolution of (3R,6R)-6-methylpiperidin-3-ol hydrochloride (115 mg, 1.00mmol) in dichloromethane (15 mL) at 0° C. Triethylamine (377 mg, 4.73mmol) was added and the mixture was allowed to warm to RT and stirredovernight. The mixture was quenched with water and extracted 3× withdichloromethane. The combined organic layers were washed with brine,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by prep-TLC (1:1 EtOAc in petroleum ether),providing the title compound. LRMS m/z (M+H) 304.1 found, 304.1required.

Step 2:(2-(2H-1,2,3-Triazol-2-yl)thiophen-3-yl)((2R,5R)-5-((4-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone

To a solution of((2R,5R)-5-hydroxy-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone(50 mg, 0.17 mmol) in DMF (2.0 mL) was added sodium hydride (60%dispersion in mineral oil, 14 mg, 0.34 mmol) at 0° C. The suspension wasstirred for 0.5 h and 4-(2,2-difluoroethoxy)-2-fluoropyridine (60 mg,0.34 mmol) was added. The reaction mixture was allowed to warm to RT andstirred for 9 h. The mixture was quenched with saturated, aqueous NH₄Cl,diluted with saturated, aqueous NaHCO₃, and extracted 3× with EtOAc. Theorganic layers were combined, washed with water and brine, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by prep-HPLC to give the title compound as a white solid. LRMSm/z (M+H) 461.1 found, 461.1 required.

EXAMPLE 65

((2R,5R)-5-(4-Ethoxypyridin-2-yloxy)-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanoneStep 1:((2R,5R)-5-(4-Bromopyridin-2-yloxy)-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone

To a solution of((2R,5R)-5-hydroxy-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone (100 mg, 0.33 mmol) in tetrahydrofuran (5 mL) was added sodiumhydride (66 mg, 1.65 mmol) at 0° C. The mixture was stirred at 0° C. for0.5 h, then 4-bromo-2-fluoropyridine (123 mg, 0.66 mmol) was added. Themixture was allowed to warm to RT and stirred for 2 h. The mixture wasquenched with water and extracted 3× with dichloromethane. The combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified byprep-TLC (1:1 EtOAc in petroleum ether), providing the title compound.LRMS m/z (M+H) 458.9 and 460.9 found, 459.0 and 461.0 required.

Step 2:((2R,5R)-5-(4-Ethoxypyridin-2-yloxy)-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone

A suspension of sodium (13 mg, 0.54 mmol) in ethanol (3 mL) was stirredat RT until the sodium was completely dissolved.((2R,5R)-5-(4-Bromopyridin-2-yloxy)-2-methylpiperidin-1-yl)(2-(pyrimidin-2-yl)thiophen-3-yl)methanone (50 mg, 0.11 mmol) was added. The resulting mixture was heatedat 80° C. overnight. After cooling to RT, the mixture was concentratedin vacuo. The residue was purified by prep-HPLC to give the titlecompound. LRMS m/z (M+H) 425.1 found, 425.1 required.

TABLE 10 The following compound was prepared using the foregoingmethodology and general procedure described in Example 65. The requisitestarting materials were commercially available, described in theliterature or readily synthesized by one skilled in the art of organicsynthesis from commerically available reagents using conventionalreactions without undue experimentation.

LRMS Example R Name (M + H⁺) 66

2-(3-{[(2R,5R)-2- methyl-5-{[4-(2,2,2- trifluoroethoxy)pyridin-2-yl]oxy} piperidin-1-yl] carbonyl}thiophen 2-yl)pyrimidineCalc'd 479.1, found 479.1

TABLE 11 The following table shows representative data for the compoundsof the Examples as orexin receptor antagonists as determined by theassays described herein. hOX2R FLIPR hOX1R FLIPR Example IC₅₀ (nM) IC₅₀(nM) 1 20.5 859 2 12.5 617 3 14.7 843 4 59.4 1851 5 15.1 669 6 19 2177 723 1198 8 35.4 2008 10 14.7 576 12 11.0 938 13 56.2 1755 14 34.8 1981 1524.5 746 17 27 1605 18 94.5 10000 19 22.1 1800 20 114 10000 21 38.3 819423 41.2 2145 24 136 10000 25 110 10000 26 37.2 2479 27 12 1418 28 8 134529 29 8074 30 38 10000 31 34 >10,000 32 24 4355 33 71 >10,000 34 42 214235 62 3269 36 56 2973 37 52 2722 38 56 2502 40 15.2 581 42 134 5611 4338.7 2490 44 67.0 1637 45 33 2944 46 63 3522 47 84 9272 48 9.7 568 49 7110,000 50 37.5 6747 51 12.3 976 52 4 194 53 8 490 54 11 1018 55 13 176056 11 1145 57 11 1690 58 21 1107 59 11 1264 60 22 2017 61 25 1479 62 221162 63 55 8381 64 36 5214 65 26 899 66 26 2080

With respect to other piperidine compounds such as those disclosed in WO2010/048012, it would be desirable that the present compounds exhibitunexpected properties, such as increased selectivity at the orexin-2receptor relative to the orexin-1 receptor. For example, relative to2-pyridyloxy compounds of WO2010/048012 that do not possess a2-pyridyloxy-4-ether substituent, the compounds of the examples possessgreater selectivity for the orexin-2 receptor than for the orexin-1receptor.

For example, the following 2-pyridyloxy compounds are disclosed in WO2010/048012:

Representative compounds herein are the compounds of Example 1, 6, 12,19, 27, 28, 31, 32, 54 and 59.

As indicated by the data herein, the compounds of the present examplesprovide greater functional selectivity for the orexin-2 receptor overthe orexin-1 receptor. The distinction in potency between the orexin-2receptor and the orexin-1 receptor in the whole cell FLIPR functionalassay provides enhanced predictive value for determining in vivoefficacy. Increasing the functional selectivity for the orexin-2receptor reduces the potential for dual receptor antagonism in vivo.Such greater functional selectivity may provide benefits over otherorexin receptor antagonists that are known in the art.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula Ia:

wherein: R^(1a), R^(1b) and R^(1c) are independently selected from thegroup consisting of: (1) hydrogen, (2) halogen, (3) hydroxyl, (4)C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxylor phenyl, (5) —O—C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, (6) —CN, and (7) 1,2,3-triazolyl, which isunsubstituted or substituted with halogen, hydroxyl, C₁₋₆alkyl,—O—C₁₋₆alkyl or —NO₂, wherein only one of R^(1a), R^(1b) and R^(1c) maybe 1,2,3-triazolyl; R³ is methyl; R⁵ is selected from the groupconsisting of: (1) C₁₋₆alkyl, which is unsubstituted or substituted withhalogen or phenyl, (2) C₃₋₆cycloalkyl, which is unsubstituted orsubstituted with C₁₋₆alkyl, halogen or phenyl, and (3) phenyl, which isunsubstituted or substituted with C₁₋₆alkyl, halogen or phenyl; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1 ora pharmaceutically acceptable salt thereof wherein R⁵ is selected fromthe group consisting of: (1) C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen or phenyl, (2) C₃₋₆cycloalkyl, which isunsubstituted or substituted with C₁₋₆alkyl or halogen, and (3) phenyl.3. The compound of claim 1 or a pharmaceutically acceptable salt thereofwherein R⁵ is selected from the group consisting of: methyl,fluoro-methyl, difluoro-methyl, ethyl, fluoroethyl, isopropyl,cyclopropyl, butyl, 2,2-difluoro-ethyl, phenyl, and benzyl.
 4. Thecompound of claim 1 or a pharmaceutically acceptable salt thereofwherein R⁵ is methyl, ethyl or isopropyl.
 5. A compound which isselected from the group consisting of:4-ethoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;3-bromo-4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;4-(benzyloxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;4-(1-methylethoxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;4-methoxy-2-{[(3R,6R)-6-methyl-1-{[4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}piperidin-3-yl]oxy}pyridine;2-{[(3R,6R)-1-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-methoxypyridine;3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)-4-(2H-1,2,3-triazol-2-yl)benzamide;2-({(3R,6R)-1-[(2-cyclopropylphenyl)carbonyl]-6-methylpiperidin-3-yl}oxy)-4-methoxypyridine;4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(trifluoromethyl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;2-({(3R,6R)-1-[(2-ethoxyphenyl)carbonyl]-6-methylpiperidin-3-yl}oxy)-4-methoxypyridine;6-methoxy-3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)-2-phenylpyridine;2-{[(3R,6R)-1-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-methoxypyridine;6-methoxy-3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)-2-(2H-1,2,3-triazol-2-yl)pyridine;2-{[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-methoxypyridine;4-methoxy-2-{[(3R,6R)-1-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}pyridine;2-cyclopropyl-6-methoxy-3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)pyridine;2-chloro-6-methoxy-3-({(2R,5R)-5-[(4-methoxypyridin-2-yl)oxy]-2-methylpiperidin-1-yl}carbonyl)pyridine;2-{[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-(1-methylethoxy)pyridine;2-{[(3R,6R)-1-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-(1-methylethoxy)pyridine;6-methoxy-3-{[(2R,5R)-2-methyl-5-{[4-(1-methylethoxy)pyridin-2-yl]oxy}piperidin-1-yl]carbonyl}-2-(2H-1,2,3-triazol-2-yl)pyridine;2-{[(3R,6R)-1-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}-4-(1-methylethoxy)pyridine;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-2-methyl-5-((4-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)piperidin-1-yl)methanone;4-(2,2-difluoroethoxy)-2-{[(3R,6R)-6-methyl-1-({2-[(methylsulfonyl)methyl]phenyl}carbonyl)-piperidin-3-yl]oxy}pyridine;1-(2-{[(2R,5R)-5-{[4-(2,2-difluoroethoxy)pyridin-2-yl]oxy}-2-methylpiperidin-1-yl]carbonyl}phenyl)cyclopropanecarbonitrile;2-{[(2R,5R)-5-{[4-(2,2-difluoroethoxy)pyridin-2-yl]oxy}-2-methylpiperidin-1-yl]carbonyl}-3-(2H-1,2,3-triazol-2-yl)pyridine;4-(2,2-difluoroethoxy)-2-{[(3R,6R)-1-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}pyridine;4-(2,2-difluoroethoxy)-2-{[(3R,6R)-1-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}pyridine;4-(2,2-difluoroethoxy)-2-{[(3R,6R)-1-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-6-methylpiperidin-3-yl]oxy}pyridine;4-(cyclopropyloxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-piperidin-3-yl]oxy}pyridine;2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-4-(oxetan-3-yloxy)pyridine;4-(2-methylpropoxy)-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridine;2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}-4-propoxypyridine;1-(4-methoxy-2-{[(3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-3-yl)ethanone;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(difluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone;(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(fluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone;and1-(2-{[(2R,5R)-5-{[4-(difluoromethoxy)pyridin-2-yl]oxy}-2-methylpiperidin-1-yl]carbonyl}-phenyl)cyclopropanecarbonitrile;or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.